This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g. "nucleotide_excision_repair_deficiency#Persistent Unexcised DNA Lesions").
The three loss-of-function nodes are alternative entry points, not a sequence. A conforming entry declares the one that matches its gene: XPC or DDB2 loss conforms to the global-genome node; ERCC6, ERCC8 or UVSSA loss to the transcription-coupled node; XPA, ERCC3, ERCC2, GTF2H5, ERCC5, ERCC4 or ERCC1 loss to the core node, because a core factor is used by both subpathways and its loss abolishes both. Xeroderma pigmentosum as a whole is defined by global-genome NER failure (every complementation group loses it), so an entry that bundles recognition and core genes into one NER node, as Xeroderma_Pigmentosum does, conforms to the global-genome node and lets the core node stand for the entries whose causal gene is a core factor (trichothiodystrophy, XFE progeroid syndrome, COFS).
Which effector arm an entry takes follows from which subpathway it has lost, not from the gene alone. Loss of a core factor removes both subpathways and an entry may conform on both arms; XPA, XPD and XPG patients develop both skin cancer and neurodegeneration. Loss of a transcription-coupled factor leaves global-genome NER intact, so Cockayne syndrome and UV-sensitive syndrome carry no mutagenic arm and no cancer excess: Ljungman and Zhang's reading is that the easily triggered apoptosis of the transcription-coupled arm eliminates pre-mutagenic cells. Conversely XPC and DDB2 loss leaves transcription-coupled NER intact and those patients have no neurological disease.
The lesion trigger carries no GO binding on purpose. The input is chemistry and exposure, not a biological process: UV photoproducts in skin, platinum and other bulky adducts, and the endogenous 8,5'-cyclopurine deoxynucleosides that are candidate neurodegenerative lesions because UV does not reach the brain. A conforming entry binds the exposure on its own node (an ECTO `triggers` term, or the entry's `environmental` block linked through `influences_mechanisms`) and may bind GO:0009411 response to UV where the trigger is sunlight, as Xeroderma_Pigmentosum does.
Deliberately outside this module: the transcription-factor functions of TFIIH and the CS proteins that are independent of repair. Trichothiodystrophy is a transcription syndrome whose photosensitive subset also loses NER; only the NER node of that entry conforms here, and its basal-transcription and R-loop nodes do not. Likewise the repair-independent roles of CSA and CSB that are the leading explanation for why Cockayne syndrome is so much more severe than UV-sensitive syndrome are not module content; they are the competing hypotheses curated in UV-Sensitive_Syndrome (csa_csb_repair_independent_functions, csb_pgbd3_fusion_position) and Cockayne_Syndrome, and this module's knowledge-gap discussion points at them. Do not add a node for them here until one is established.
Why does loss of the same transcription-coupled initiation step produce only photosensitivity in UV-sensitive syndrome but neurodegeneration and segmental progeria in Cockayne syndrome, and does the degenerative consequence of this module therefore depend on a repair-independent function of CSA and CSB that it does not model?
KNOWLEDGE GAP
tc_ner_loss_severity_divergence
Attached to:
Transcription Stress-Induced Cell Death and Senescence
Neurodegeneration and Segmental Progeroid Degeneration
The module's transcription-coupled arm is supported by the shared cellular phenotype of UV-sensitive and Cockayne syndrome cells, but the clinical outcomes diverge completely, and the cell-death effector alone cannot account for that. The leading explanations (repair-independent roles of CSB and CSA in transcription by RNA polymerases I and II, in oxidative damage handling and in mitochondria, and the position of the CSB-PGBD3 fusion) are curated as competing hypotheses in UV-Sensitive_Syndrome and Cockayne_Syndrome, not as module nodes. Until one of them is established, conforming entries should treat the degenerative consequence as disease-specific and keep the module's claim to the shared repair failure.
Global-Genome NER Failure
trigger
Global-genome nucleotide excision repair surveys the whole genome for helix-distorting lesions and is initiated by XPC-RAD23B, assisted at UV photoproducts by the UV-DDB complex (DDB2). Loss of either recognition factor leaves transcription-coupled repair intact but abolishes removal of lesions from non-transcribed DNA and from the non-transcribed strand of active genes; loss of a core factor (next node) abolishes it as well. This is the subpathway whose failure defines xeroderma pigmentosum.
Downstream
-
Persistent Unexcised DNA Lesions
Without global-genome recognition, helix-distorting lesions outside transcribed strands are never presented to the excision machinery and persist genome-wide until replication reaches them.
Show evidence (3 references)
"Using a novel DNA damage recognition-competition assay, we identified XPC-HR23B as the earliest damage detector to initiate NER: it acts before the known damage-binding protein XPA."
Establishes XPC as the initiating recognition factor of the global-genome subpathway, so its loss is a failure at the first step modeled here.
"GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein)."
Names the two subpathway-specific recognition factors whose genes (XPC, DDB2) this node carries. Evidence source is OTHER because this is a review.
"The global genome NER (GG-NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death."
States the division of labour between the two subpathways that the two loss-of-function nodes and the two effector arms of this module follow. Evidence source is OTHER because this is a review.
Transcription-Coupled NER Initiation Failure at Stalled RNA Polymerase II
trigger
Transcription-coupled nucleotide excision repair is initiated when elongating RNA polymerase II stalls at a lesion in the transcribed strand; CSB (ERCC6) is recruited to the stalled polymerase, CSA (ERCC8) and UVSSA-USP7 stabilise CSB and process the stalled polymerase, and the core machinery is then recruited. Loss of CSB, CSA or UVSSA leaves global-genome repair intact but abolishes the preferential, rapid removal of transcription-blocking lesions, so that a stalled polymerase itself becomes the persistent problem.
Used by disorders
COFS Syndrome
as Defective Transcription-Coupled Nucleotide Excision Repair
Downstream
-
Persistent Unexcised DNA Lesions
Without transcription-coupled initiation, lesions in the transcribed strand of active genes are removed only slowly, if global-genome repair reaches them, and stalled RNA polymerase II remains at the lesion.
Show evidence (4 references)
"To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription."
Defines the subpathway and the stalled-transcription trigger that this node's factors act on. Evidence source is OTHER because this is a review.
"Damage detection by stalling of the transcribing Pol II is highly efficient, but a stalled Pol II complex may create an even bigger problem by interfering with repair of the lesions, and overall with transcription and replication."
Explains why failure at this step is more than a missed repair: the stalled polymerase is itself an obstacle. Evidence source is OTHER because this is a review.
"The UVSSA protein interacts with elongating RNA polymerase II, localizes specifically to UV-induced lesions, resides in chromatin-associated TC-NER complexes and is implicated in stabilizing the TC-NER master organizing protein ERCC6 (also known as CSB) by delivering the deubiquitinating enzyme..."
Places UVSSA in the same initiation complex as CSB and shows the CSB-stabilising role that makes UVSSA loss a failure of the same step.
+ 1 more reference
Core NER Lesion Verification and Dual Incision Failure
trigger
Both subpathways converge on one excision machinery. TFIIH is recruited to the recognised lesion, its XPB subunit opens the helix and its XPD subunit tracks until it stalls at the lesion and verifies it; XPA, RPA and XPG then assemble the preincision complex, and ERCC1-XPF incises 5' and XPG 3' of the lesion to release a roughly 30-nucleotide oligonucleotide. Loss of any core factor (XPA, ERCC3/XPB, ERCC2/XPD, GTF2H5/TTDA, ERCC5/XPG, ERCC4/XPF, ERCC1) abolishes excision downstream of either recognition route, so these patients lose both global-genome and transcription-coupled repair. TFIIH also serves transcription initiation and ERCC1-XPF also serves interstrand-crosslink repair, so loss of those factors adds consequences this module does not model.
Downstream
-
Persistent Unexcised DNA Lesions
With the shared excision machinery lost, lesions reached by either recognition route are verified or incised inefficiently or not at all, so both the genome-wide and the transcribed-strand lesion burdens persist.
Show evidence (5 references)
"Stalling of XPD at the lesion allows for the formation of the preincision complex by recruitment of XPA, RPA, and XPG."
Describes the verification and preincision-assembly step that the core factors carry out after either recognition route. Evidence source is OTHER because this is a review.
"After this subpathway-specific initial lesion detection, XPA may function as a common damage verifier and adaptor to the core of the NER apparatus."
Positions XPA as the common verifier downstream of both subpathway-specific detection routes, which is what makes this node the shared core.
"Following damage recognition, dual incision 5' to the lesion by ERCC1-XPF and 3' to the lesion by XPG leads to the removal of a lesion-containing oligonucleotide of about 30 nucleotides."
Defines the dual-incision step and the two endonucleases whose loss ends excision regardless of how the lesion was found.
+ 2 more references
Persistent Unexcised DNA Lesions
central effector
The key conformance target. Whichever route was lost, the consequence is a lesion that nucleotide excision repair should have removed and did not: genome-wide after global-genome failure, concentrated in the transcribed strands of active genes after transcription-coupled failure, both after core-factor loss. The persistent lesion signals as ongoing DNA damage and is the substrate for the two effector arms, which fate depends on whether the cell meets it with a replication fork or with an elongating RNA polymerase. Conforming entries name the lesion class and compartment that applies to them (UV photoproducts in epidermis, endogenous cyclopurines in neurons, platinum adducts after chemotherapy).
Used by disorders
COFS Syndrome
as Accumulation of Transcription-Blocking DNA Lesions
Downstream
-
Mutagenic Replication Across Persistent Lesions
A persistent lesion met by a replication fork is bypassed rather than removed, and the bypass fixes the lesion as a mutation; this arm is open to entries that have lost global-genome repair.
-
Transcription Stress-Induced Cell Death and Senescence
A persistent lesion in a transcribed strand stalls RNA polymerase II; the stalled polymerase triggers apoptosis or senescence. This arm is open to entries that have lost transcription-coupled repair, and to core-factor entries in post-mitotic tissue.
Show evidence (3 references)
"Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction."
The lesions this node holds are exactly those the cut-and-patch reaction would otherwise eliminate. Evidence source is OTHER because this is a review.
"In the absence of NER, the damage accumulates, causing neuronal death by blocking transcription."
States the accumulation of unrepaired damage in the absence of NER that this node represents, and previews the transcription-blockage arm. Evidence source is OTHER because this is a review.
"We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension."
Shows in ERCC1-XPF-deficient mice that the unrepaired-damage state is itself signalled systemically, the organism-level reading of the persistent-lesion node.
Mutagenic Replication Across Persistent Lesions
effector
When replication reaches an unrepaired helix-distorting lesion the fork bypasses it by translesion synthesis. Bypass of UV photoproducts yields the characteristic C-to-T transitions and CC-to-TT tandem substitutions at dipyrimidine sites (the UV signature), and the mutation burden accumulates with every exposure. This is the global-genome effector arm; it requires a dividing cell, so it is expressed in epidermis and other renewing tissues and not in post-mitotic neurons. Conforming entries name the exposure and the tissue; xeroderma pigmentosum variant (POLH loss) enters this node directly, with intact excision but error-prone bypass.
Downstream
-
Mutagenesis-Driven Carcinogenesis
Accumulated signature mutations in proliferating cells of the exposed tissue drive clonal transformation.
Show evidence (2 references)
"A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT."
Defines the mutation signature that bypass of unrepaired UV photoproducts leaves, the measurable output of this node. Evidence source is OTHER because this is a review and meta-analysis.
"Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome."
The cancer predisposition that follows GG-NER loss is the downstream of this mutagenic arm, and the contrast with TC-NER loss is why the two arms are separate nodes. Evidence source is OTHER because this is a review.
Transcription Stress-Induced Cell Death and Senescence
effector
An elongating RNA polymerase II stalled at an unrepaired transcribed-strand lesion suppresses global transcription, stabilises p53 and triggers apoptosis at lesion doses that a repair-proficient cell tolerates; cells that survive enter senescence. This is the transcription-coupled effector arm. It is expressed in any cell, including post-mitotic neurons, and does not need replication. Conforming entries name the cell type and the stress that applies: UV-irradiated keratinocytes in the skin of UV-sensitive and Cockayne syndrome patients, endogenous-lesion-stressed neurons in neurodegenerative NER disease, senescent fibroblasts in the progeroid syndromes.
Downstream
-
Neurodegeneration and Segmental Progeroid Degeneration
Cumulative loss and senescence of cells that cannot be replaced, above all neurons and oligodendroglia, together with the systemic response to unrepaired damage, produce the degenerative and progeroid consequence.
Show evidence (3 references)
"It was found that cells from patients with Cockayne's syndrome, which are deficient in the processing of u.v.-induced pyrimidine dimers from the transcribed DNA strand, are induced to undergo apoptosis at much lower doses of u.v. light than cells with proficient strand-specific repair."
Direct demonstration that losing transcribed-strand repair lowers the apoptotic threshold, the cell-death reading of this node.
"In addition, lesions may block transcription, which causes disturbed cellular homeostasis and may trigger cellular senescence or apoptosis, resulting in damage-induced aging."
Names both cell fates this node carries and links them to the damage-induced ageing that the consequence node describes. Evidence source is OTHER because this is a review.
"These findings may help explain a long standing enigma of why, despite the DNA repair deficiency, patients with Cockayne's syndrome do not experience an elevated risk for skin cancer since potentially pre-mutagenic cells are eliminated by an easily triggered apoptotic pathway."
Explains why entries on this arm carry no mutagenic arm: the cell-death effector removes the cells that would otherwise be mutated.
Mutagenesis-Driven Carcinogenesis
consequence
Clonal expansion of cells carrying accumulated signature mutations in the exposed, proliferating tissue. For UV this is the skin and ocular surface, where keratinocytes and melanocytes give rise to basal cell carcinoma, squamous cell carcinoma and melanoma at an age and rate far beyond the general population. Conforming entries substitute the tissue and tumour types; a neoplasm entry curating the resulting tumour should conform to the hallmarks-of-cancer modules instead, since this node ends at transformation.
Show evidence (2 references)
"Deficiencies in NER are associated with the extremely skin cancer-prone inherited disorder xeroderma pigmentosum."
The skin-cancer proneness of xeroderma pigmentosum is the clinical face of this consequence. Evidence source is OTHER because this is a review.
"Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome."
Ties cancer predisposition specifically to the global-genome arm that feeds this node. Evidence source is OTHER because this is a review.
Neurodegeneration and Segmental Progeroid Degeneration
consequence
The tissue and organism consequence of the transcription-coupled arm: progressive loss of neurons and myelin producing the neurodegeneration of Cockayne syndrome, COFS and neurological xeroderma pigmentosum, and the segmental progeroid picture (growth failure, cachexia, sensorineural deafness, retinopathy, suppressed somatotroph axis, early death) of Cockayne syndrome and XFE progeroid syndrome. Which features appear, and how severely, varies with the factor lost and the residual activity of the allele; UV-sensitive syndrome, which loses the same transcription-coupled initiation step, does not reach this node at all, which is the open question recorded in the discussion below.
Show evidence (3 references)
"Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome."
The premature-ageing end of the TC-NER-deficiency spectrum is this consequence node. Evidence source is OTHER because this is a review.
"Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients' death in early adulthood."
Records the multisystem degenerative outcome and early death that the node describes. Evidence source is OTHER because this is a review.
"A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms."
The XFE index patient shows that core-factor loss reaches this progeroid consequence in a human.