期刊
SCIENCE ADVANCES
卷 7, 期 21, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf2278
关键词
-
资金
- ALW OPEN from the Netherlands Organization for Scientific Research for Earth and Life Sciences [OP.393]
The research reveals that through de novo DNA synthesis and the specific protein complex, DNA loss can be suppressed and deletion mutagenesis can be limited at sites of stalled replication, protecting Okazaki fragments from resection by EXO1.
During genome duplication, the replication fork encounters a plethora of obstacles in the form of damaged bases, DNA-cross-linked proteins, and secondary structures. How cells protect DNA integrity at sites of stalled replication is currently unknown. Here, by engineering primase deserts into the Caenorhabditis elegans genome close to replication-impeding G-quadruplexes, we show that de novo DNA synthesis downstream of the blocked fork suppresses DNA loss. We next identify the pol alpha-primase complex to limit deletion mutagenesis, a conclusion substantiated by whole-genome analysis of animals carrying mutated POLA2/DIV-1. We subsequently identify a new role for the 9-1-1 checkpoint clamp in protecting Okazaki fragments from resection by EXO1. Together, our results provide a mechanistic model for controlling the fate of replication intermediates at sites of stalled replication.
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