期刊
NUCLEIC ACIDS RESEARCH
卷 47, 期 19, 页码 10181-10201出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz769
关键词
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资金
- National Institutes of Health/National Cancer Institute (NIH/NCI) [P01CA193124]
- Cancer Prevention & Research Institute of Texas [RP160667]
- NIH [P01 CA193124, CA157448, CA210929, CA216911, CA216437, P01 CA092584. NIH R35 CA220430]
- Pamela and Wayne Garrison Distinguished Chair in Cancer Research
- Robert A. Welch Chemistry Chair
- Cancer Prevention and Research Institute of Texas
- NIH/NCI [P30CA016672]
Interstrand crosslinks (ICLs) are highly toxic DNA lesions that are repaired via a complex process requiring the coordination of several DNA repair pathways. Defects in ICL repair result in Fanconi anemia, which is characterized by bone marrow failure, developmental abnormalities, and a high incidence of malignancies. SLX4, also known as FANCP, acts as a scaffold protein and coordinates multiple endonucleases that unhook ICLs, resolve homologous recombination intermediates, and perhaps remove unhooked ICLs. In this study, we explored the role of SLX4IP, a constitutive factor in the SLX4 complex, in ICL repair. We found that SLX4IP is a novel regulatory factor; its depletion sensitized cells to treatment with ICL-inducing agents and led to accumulation of cells in the G2/M phase. We further discovered that SLX4IP binds to SLX4 and XPF-ERCC1 simultaneously and that disruption of one interaction also disrupts the other. The binding of SLX4IP to both SLX4 and XPF-ERCC1 not only is vital for maintaining the stability of SLX4IP protein, but also promotes the interaction between SLX4 and XPF-ERCC1, especially after DNA damage. Collectively, these results demonstrate a new regulatory role for SLX4IP in maintaining an efficient SLX4-XPF-ERCC1 complex in ICL repair.
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