Journal
CELL CYCLE
Volume 13, Issue 13, Pages 2120-2128Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.29157
Keywords
DNA replication; replicaiton fork integrity; heterochromatin; centromeres; histone deacetylase; Xenopus laevis
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Funding
- Cancer Research UK
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- European Research Council (ERC) [206281]
- Lister Institute of Preventive Medicine
- EMBO
- Association for International Cancer Research (AICR)
- Giovanni-Armenise award
- Epigen Progetto Bandiera
- Fondazione Telethon
- European Research Council (ERC) [206281] Funding Source: European Research Council (ERC)
- Worldwide Cancer Research [13-0026] Funding Source: researchfish
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Orderly progression of S phase requires the action of replisome-associated Tipin and Tim1 proteins, whose molecular function is poorly understood. Here, we show that Tipin deficiency leads to the accumulation of aberrant replication intermediates known as reversed forks. We identified Mta2, a subunit of the NuRD chromatin remodeler complex, as a novel Tipin binding partner and mediator of its function. Mta2 is required for Tipin-dependent Polymerase a binding to replicating chromatin, and this function is essential to prevent the accumulation of reversed forks. Given the role of the Mta2-NuRD complex in the maintenance of heterochromatin, which is usually associated with hard-to-replicate DNA sequences, we tested the role of Tipin in the replication of such regions. Using a novel assay we developed to monitor replication of specific genomic loci in Xenopus laevis egg extract we demonstrated that Tipin is directly required for efficient replication of vertebrate centromeric DNA. Overall these results suggest that Mta2 and Tipin cooperate to maintain replication fork integrity, especially on regions that are intrinsically difficult to duplicate.
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