Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0002871 (
anemia
)
52,094
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cells often use multiple pathways to repair the same DNA lesion, and the choice of pathway has substantial implications for the fidelity of genome maintenance. DNA interstrand crosslinks covalently link the two strands of DNA, and thereby block replication and transcription; the cytotoxicity of these crosslinks is exploited for chemotherapy. In Xenopus egg extracts, the collision of replication forks with interstrand crosslinks initiates two distinct repair pathways. NEIL3 glycosylase can cleave the crosslink
1
; however, if this fails, Fanconi
anaemia
proteins incise the phosphodiester backbone that surrounds the interstrand crosslink, generating a double-strand-break intermediate that is repaired by homologous recombination
2
. It is not known how the simpler NEIL3 pathway is prioritized over the Fanconi
anaemia
pathway, which can cause genomic rearrangements. Here we show that the E3 ubiquitin ligase
TRAIP
is required for both pathways. When two replisomes converge at an interstrand crosslink,
TRAIP
ubiquitylates the replicative DNA helicase CMG (the complex of CDC45, MCM2-7 and GINS). Short ubiquitin chains recruit NEIL3 through direct binding, whereas longer chains are required for the unloading of CMG by the p97 ATPase, which enables the Fanconi
anaemia
pathway. Thus,
TRAIP
controls the choice between the two known pathways of replication-coupled interstrand-crosslink repair. These results, together with our other recent findings
3,4
establish
TRAIP
as a master regulator of CMG unloading and the response of the replisome to obstacles.
...
PMID:TRAIP is a master regulator of DNA interstrand crosslink repair. 3084 57
The NEIL3 DNA glycosylase is a base excision repair enzyme that excises bulky base lesions from DNA. Although NEIL3 has been shown to unhook interstrand crosslinks (ICL) in Xenopus extracts, how NEIL3 participants in ICL repair in human cells and its corporation with the canonical Fanconi
anemia
(FA)/BRCA pathway remain unclear. Here we show that the NEIL3 and the FA/BRCA pathways are non-epistatic in psoralen-ICL repair. The NEIL3 pathway is the major pathway for repairing psoralen-ICL, and the FA/BRCA pathway is only activated when NEIL3 is not present. Mechanistically, NEIL3 is recruited to psoralen-ICL in a rapid, PARP-dependent manner. Importantly, the NEIL3 pathway repairs psoralen-ICLs without generating double-strand breaks (DSBs), unlike the FA/BRCA pathway. In addition, we found that the RUVBL1/2 complex physically interact with NEIL3 and function within the NEIL3 pathway in psoralen-ICL repair. Moreover,
TRAIP
is important for the recruitment of NEIL3 but not FANCD2, and knockdown of
TRAIP
promotes FA/BRCA pathway activation. Interestingly,
TRAIP
is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that
TRAIP
may function upstream of the two pathways. Taken together, the NEIL3 pathway is the major pathway to repair psoralen-ICL through a unique DSB-free mechanism in human cells.
...
PMID:Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair. 3198 Aug 15
