Preservation of lagging strand integrity at sites of stalled replication by Pol α-primase and 9-1-1 complex.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34138739.
- Also identified by DOI 10.1126/sciadv.abf2278 and PMC identifier 8133754.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 <i>Caenorhabditis elegans</i> 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 α-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.