AI Article Synopsis
- Replication fork-associated factors are crucial for maintaining genome stability and may help prevent cancer.
- Mutations in the DDX11 helicase and ESCO2 acetyltransferase lead to cohesinopathies, a group of developmental disorders.
- Our research shows that while DDX11 and Tim-Tipin are essential for compensating ESCO2 loss during chromosome segregation, defects in centromeric cohesion don't always cause chromosome missegregation, suggesting issues with inner-centromere phosphorylation impact both processes.
Article Abstract
Replication fork-associated factors promote genome integrity and protect against cancer. Mutations in the DDX11 helicase and the ESCO2 acetyltransferase also cause related developmental disorders classified as cohesinopathies. Here we generated vertebrate model cell lines of these disorders and cohesinopathies-related genes. We found that vertebrate DDX11 and Tim-Tipin are individually needed to compensate for ESCO2 loss in chromosome segregation, with DDX11 also playing complementary roles with ESCO2 in centromeric cohesion. Our study reveals that overt centromeric cohesion loss does not necessarily precede chromosome missegregation, while both these problems correlate with, and possibly originate from, inner-centromere defects involving reduced phosphorylation of histone H3T3 (pH3T3) in the region. Interestingly, the mitotic pH3T3 mark was defective in all analyzed replication-related mutants with functions in cohesion. The results pinpoint mitotic pH3T3 as a postreplicative chromatin mark that is sensitive to replication stress and conducts with different kinetics to robust centromeric cohesion and correct chromosome segregation.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356530 | PMC |
| http://dx.doi.org/10.18632/oncotarget.11982 | DOI Listing |
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