Premium
Repair pathway crosstalk in genome stability maintenance through BRCA1/2‐mediated homologous recombination (352.1)
Author(s) -
Cooper Priscilla,
Trego Kelly,
Groesser Torsten,
Parplys Ann,
Cmielova Jana,
Wiese Claudia,
Sung Patrick,
Campisi Judith
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.352.1
Subject(s) - genome instability , biology , rad51 , nucleotide excision repair , dna repair , homologous recombination , dna damage , chromatin , cockayne syndrome , xeroderma pigmentosum , microbiology and biotechnology , base excision repair , genetics , dna
XPG is an endonuclease required for nucleotide excision repair with important non‐enzymatic roles in base excision repair (BER) and transcription‐coupled repair (TCR). XPG enzymatic defects cause cancer‐prone xeroderma pigmentosum (XP), while truncating mutations cause the progeroid disorder Cockayne syndrome (CS). We now reveal an unexpected XPG role in homologous recombination (HR). XPG loss elevates the DNA damage response and causes double‐strand break (DSB) formation with pronounced genomic instability. XPG knockdown (KD) cells have impaired recovery from replicative stress, and DNA fiber analysis reveals inability to restart stalled replication forks. XPG interacts directly with the HR proteins RAD51, BRCA2, and PALB2 in a stable complex, and XPG KD results in their reduced chromatin loading and in decreased HR at site‐specific DSBs. Placing its role in HR upstream of BRCA2, XPG KD also reduces single‐strand annealing and increases chromatin‐bound BRCA1 and BRCA1 foci. Thus, loss of XPG function impairs replication fork maintenance by HR and may be important in BRCA‐associated cancers. It also accelerates aging, leading to cellular senescence or apoptosis and to severe progeria in XP‐G/CS patients and a mouse model. Whether this accelerated aging is related to XPG roles in TCR, BER, or HR remains to be determined.