New histone supply regulates replication fork speed and PCNA unloading

TY - JOUR

T1 - New histone supply regulates replication fork speed and PCNA unloading

AU - Mejlvang, Jakob

AU - Feng, Yunpeng

AU - Alabert, Constance

AU - Neelsen, Kai J

AU - Jasencakova, Zusana

AU - Zhao, Xiaobei

AU - Lees, Michael

AU - Sandelin, Albin

AU - Pasero, Philippe

AU - Lopes, Massimo

AU - Groth, Anja

PY - 2014/1/6

Y1 - 2014/1/6

N2 - Correct duplication of DNA sequence and its organization into chromatin is central to genome function and stability. However, it remains unclear how cells coordinate DNA synthesis with provision of new histones for chromatin assembly to ensure chromosomal stability. In this paper, we show that replication fork speed is dependent on new histone supply and efficient nucleosome assembly. Inhibition of canonical histone biosynthesis impaired replication fork progression and reduced nucleosome occupancy on newly synthesized DNA. Replication forks initially remained stable without activation of conventional checkpoints, although prolonged histone deficiency generated DNA damage. PCNA accumulated on newly synthesized DNA in cells lacking new histones, possibly to maintain opportunity for CAF-1 recruitment and nucleosome assembly. Consistent with this, in vitro and in vivo analysis showed that PCNA unloading is delayed in the absence of nucleosome assembly. We propose that coupling of fork speed and PCNA unloading to nucleosome assembly provides a simple mechanism to adjust DNA replication and maintain chromatin integrity during transient histone shortage.

AB - Correct duplication of DNA sequence and its organization into chromatin is central to genome function and stability. However, it remains unclear how cells coordinate DNA synthesis with provision of new histones for chromatin assembly to ensure chromosomal stability. In this paper, we show that replication fork speed is dependent on new histone supply and efficient nucleosome assembly. Inhibition of canonical histone biosynthesis impaired replication fork progression and reduced nucleosome occupancy on newly synthesized DNA. Replication forks initially remained stable without activation of conventional checkpoints, although prolonged histone deficiency generated DNA damage. PCNA accumulated on newly synthesized DNA in cells lacking new histones, possibly to maintain opportunity for CAF-1 recruitment and nucleosome assembly. Consistent with this, in vitro and in vivo analysis showed that PCNA unloading is delayed in the absence of nucleosome assembly. We propose that coupling of fork speed and PCNA unloading to nucleosome assembly provides a simple mechanism to adjust DNA replication and maintain chromatin integrity during transient histone shortage.

U2 - 10.1083/jcb.201305017

DO - 10.1083/jcb.201305017

M3 - Journal article

C2 - 24379417

SN - 0021-9525

VL - 204

SP - 29

EP - 43

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 1

ER -