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.
Highlights
Various stressful conditions and difficult-toreplicate regions encountered during DNA replication need specialized replication factors to preserve genome stability
Our work reveals that the evolutionarily conserved Tim-Tipin fork protection complex, DDX11 helicase and ESCO2 acetyltransferase collaborate in several respects relevant for chromosome structure and genome integrity
In the context of chromatid cohesion, our findings indicate that DDX11 and ESCO2 are critical for centromeric cohesion, in which context they play partially overlapping roles, being able to compensate for each other to prevent overt centromeric separation (Figure 3B-3E)
Summary
Various stressful conditions and difficult-toreplicate regions encountered during DNA replication need specialized replication factors to preserve genome stability. Examples of factors with variegated roles during DNA replication include the replication fork protection complex, composed of Tim ( known as Timeless) and Tipin [3], and the DDX11/ChlR1 helicase [4]. These factors interact with each other and jointly affect SCC in human cells [5, 6]. Mutants in many replication forkassociated cohesion factors show reduced acetylated Smc in budding yeast [13,14,15] This observation can be explained by a multitude of mechanisms, including defects in cell cycle, altered residence time of cohesin on chromatin, and/or reduced accessibility of the Eco acetyltransferase to cohesin. Our findings pinpoint the mitotic pH3T3 at the inner-centromere as a good indicator of cohesion insufficiency and reveal the kinetics by which certain forms of replication stress negatively influence chromosome stability in mitosis
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