Journal
NUCLEIC ACIDS RESEARCH
Volume 44, Issue 22, Pages 10676-10690Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw858
Keywords
-
Categories
Funding
- Spanish Ministry of Science and Innovation [RYC-2010-07131, BFU2011-24909]
- Spanish Ministry of Economy and Competitiveness [BFU2014-52529-R]
- European Community's 7th Framework Programme [293770]
- Spanish National Research Council (CSIC) [PII-201410I001]
- Italian Foundation for Cancer Research (F.I.R.C.)
- Education Council of the Castilla y Leon regional government Spanish
- Spanish Formacion del Personal Investigador (FPI) programme
- European Union
Ask authors/readers for more resources
Problems during DNA replication underlie genomic instability and drive malignant transformation. The DNA damage checkpoint stabilizes stalled replication forks thus counteracting aberrant fork transitions, DNA breaks and chromosomal rearrangements. We analyzed fork processing in checkpoint deficient cells by coupling psoralen crosslinking with replication intermediate two-dimensional gel analysis. This revealed a novel role for Exo1 nuclease in resecting reversed replication fork structures and counteracting the accumulation of aberrant intermediates resembling fork cleavage products. Genetic analyses demonstrated a functional interplay of Exo1 with Mus81, Dna2 and Sae2 nucleases in promoting cell survival following replication stress, suggestive of concerted nucleolytic processing of stalled forks. While Mus81 and other Structure Specific Endonucleases do not contribute to obvious collapsed fork transitions, Dna2 promotes reversed fork resection likely by facilitating Exo1 access to nascent strands. Instead, Sae2 cooperates with Exo1 in counteracting putative fork cleavage events linked to double strand breaks formation and increased gross chromosomal rearrangement rates. Our data indicate that in checkpoint deficient cells diverse nuclease activities interface to eliminate aberrant replication intermediates and prevent chromosome instability.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available