Multivalent interaction of ESCO2 with the replication machinery is required for sister chromatid cohesion in vertebrates

Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1081-1089. doi: 10.1073/pnas.1911936117. Epub 2019 Dec 26.

Abstract

The tethering together of sister chromatids by the cohesin complex ensures their accurate alignment and segregation during cell division. In vertebrates, sister chromatid cohesion requires the activity of the ESCO2 acetyltransferase, which modifies the Smc3 subunit of cohesin. It was shown recently that ESCO2 promotes cohesion through interaction with the MCM replicative helicase. However, ESCO2 does not significantly colocalize with the MCM complex, suggesting there are additional interactions important for ESCO2 function. Here we show that ESCO2 is recruited to replication factories, sites of DNA replication, through interaction with PCNA. We show that ESCO2 contains multiple PCNA-interaction motifs in its N terminus, each of which is essential to its ability to establish cohesion. We propose that multiple PCNA-interaction motifs embedded in a largely flexible and disordered region of the protein underlie the unique ability of ESCO2 to establish cohesion between sister chromatids precisely as they are born during DNA replication.

Keywords: DNA replication; chromosome biology; cohesin; sister chromatid cohesion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / metabolism*
  • Animals
  • Cell Cycle Proteins / metabolism
  • Chondroitin Sulfate Proteoglycans / metabolism
  • Chromatids / metabolism*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Chromosome Segregation / physiology*
  • DNA Helicases / metabolism
  • DNA Replication / physiology*
  • HeLa Cells
  • Humans
  • Nuclear Proteins / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism
  • Vertebrates / genetics

Substances

  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromosomal Proteins, Non-Histone
  • Nuclear Proteins
  • Proliferating Cell Nuclear Antigen
  • SMC3 protein, human
  • Saccharomyces cerevisiae Proteins
  • cohesins
  • Acetyltransferases
  • ECO1 protein, S cerevisiae
  • ESCO1 protein, human
  • ESCO2 protein, human
  • DNA Helicases