The nucleotide excision repair enzyme XPG has a noncatalytic role in HRR and genomic stability.

  • Major finding: The nucleotide excision repair enzyme XPG has a noncatalytic role in HRR and genomic stability.

  • Mechanism: XPG induces the release of BRCA1 from chromatin and loads BRCA2, RAD51, and PALB2 on chromatin.

  • Impact: XPG may function as a tumor suppressor in BRCA-associated cancers.

The lack of coordination between DNA replication and DNA repair of DNA lesions results in the occurrence of stalled replication forks, which can promote genomic instability and numerous diseases, including cancer. Stalled replication forks, which cause DNA double-strand breaks (DSB), are primarily rescued by homologous recombination repair (HRR), which is initiated by the binding of BRCA1 to DSBs and requires the recruitment of RAD51 to single-stranded DNA (ssDNA) by BRCA2 in complex with partner and localizer of BRCA2 (PALB2). Nucleotide excision repair (NER) is an important mechanism for repairing ssDNA lesions and requires the endonuclease XPG (encoded by ERCC5), which is also required for postnatal mammalian development for reasons that are unclear. Trego and colleagues examined the effects of XPG depletion in vitro and discovered that transient knockdown of XPG resulted in DSBs and genomic instability that were not due to the loss of NER. Treatment of cells depleted of XPG or wild-type cells with camptothecin, which induces replication stress, resulted in increased DSBs and the upregulation of XPG, respectively. Consistent with these findings, treatment of cells depleted of XPG or wild-type cells with hydroxyurea, which arrests replication forks, resulted in an increased frequency of stalled replication forks in the former and the accumulation of XPG at DSBs in the latter. Coimmunoprecipitation of XPG and HRR proteins showed that XPG strongly binds to BRCA2 and PALB2, individually and as a trimeric complex, and to BRCA1. Mechanistically, XPG promoted HRR by driving the release of BRCA1 from chromatin and inducing chromatin loading of RAD51, BRCA2, and PALB2 after replication stress. Taken together, these results show that XPG is crucial for HRR and genomic stability and suggest a potential tumor suppressor role for XPG in BRCA-related cancers.

Trego KS, Groesser T, Davalos AR, Parplys AC, Zhao W, Nelson MR, et al. Non-catalytic roles for XPG with BRCA1 and BRCA2 in homologous recombination and genome stability. Mol Cell 2016 Jan 28 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.