MMS22L-TONSL functions in sister chromatid cohesion in a pathway parallel to DSCC1-RFC

The leading strand-oriented alternative PCNA clamp loader DSCC1-RFC functions in DNA replication, repair, and sister chromatid cohesion (SCC), but how it facilitates these processes is incompletely understood. Here, we confirm that loss of human DSCC1 results in reduced fork speed, increased DNA dam...

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Bibliographic Details
Published in:Life science alliance 2023-02, Vol.6 (2), p.e202201596
Main Authors: van Schie, Janne Jm, de Lint, Klaas, Pai, Govind M, Rooimans, Martin A, Wolthuis, Rob Mf, de Lange, Job
Format: Article
Language:English
Subjects:
Cell Cycle Checkpoints
Chromatids - genetics
Chromatids - metabolism
Chromosome Segregation - genetics
DEAD-box RNA Helicases - metabolism
DNA Damage - genetics
DNA Helicases - genetics
DNA Polymerase III - genetics
DNA Replication - genetics
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Humans
NF-kappa B - metabolism
Nucleoproteins - genetics
Nucleoproteins - metabolism
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Summary:The leading strand-oriented alternative PCNA clamp loader DSCC1-RFC functions in DNA replication, repair, and sister chromatid cohesion (SCC), but how it facilitates these processes is incompletely understood. Here, we confirm that loss of human DSCC1 results in reduced fork speed, increased DNA damage, and defective SCC. Genome-wide CRISPR screens in DSCC1-KO cells reveal multiple synthetically lethal interactions, enriched for DNA replication and cell cycle regulation. We show that DSCC1-KO cells require POLE3 for survival. Co-depletion of DSCC1 and POLE3, which both interact with the catalytic polymerase ε subunit, additively impair DNA replication, suggesting that these factors contribute to leading-strand DNA replication in parallel ways. An additional hit is MMS22L, which in humans forms a heterodimer with TONSL. Synthetic lethality of DSCC1 and MMS22L-TONSL likely results from detrimental SCC loss. We show that MMS22L-TONSL, like DDX11, functions in a SCC establishment pathway parallel to DSCC1-RFC. Because both DSCC1-RFC and MMS22L facilitate ESCO2 recruitment to replication forks, we suggest that distinct ESCO2 recruitment pathways promote SCC establishment following either cohesin conversion or de novo cohesin loading.
ISSN:2575-1077
2575-1077
DOI:10.26508/lsa.202201596