Abstract
DNA replication transforms cohesin rings dynamically associated with chromatin into the cohesive form to establish sister-chromatid cohesion. Here, we show that, in human cells, cohesin loading onto chromosomes during early S phase requires the replicative helicase MCM2-7 and the kinase DDK. Cohesin and its loader SCC2/4 (NIPBL/MAU2 in humans) associate with DDK and phosphorylated MCM2-7. This binding does not require MCM2-7 activation by CDC45 and GINS, but its persistence on activated MCM2-7 requires fork-stabilizing replisome components. Inactivation of these replisome components impairs cohesin loading and causes interphase cohesion defects. Interfering with Okazaki fragment processing or nucleosome assembly does not impact cohesion. Therefore, MCM2-7-coupled cohesin loading promotes cohesion establishment, which occurs without Okazaki fragment maturation. We propose that the cohesin-loader complex bound to MCM2-7 is mobilized upon helicase activation, transiently held by the replisome, and deposited behind the replication fork to encircle sister chromatids and establish cohesion.
Highlights
Sister-chromatid cohesion is essential for proper chromosome segregation and faithful transmission of the genome during the cell cycle (Morales and Losada, 2018; Uhlmann, 2016)
Our results show that MCM2–7 and DBF4dependent kinase (DDK) physically interact with NIPBL/MAU2 and cohesin, and are required for cohesin loading in human cells during early S phase
We propose that cohesin and NIPBL/MAU2 loaded at replication origins remain associated with MCM2–7 and DDK, and are mobilized upon replication initiation, held transiently by replisome components, and deposited behind the replication fork to establish sister-chromatid cohesion
Summary
Sister-chromatid cohesion is essential for proper chromosome segregation and faithful transmission of the genome during the cell cycle (Morales and Losada, 2018; Uhlmann, 2016). Sister-chromatid cohesion is mediated by cohesin, a ring-shaped ATPase machine that consists of SMC1A, SMC3, RAD21, and either STAG1 or STAG2 in human somatic cells (Haarhuis et al, 2014; Losada and Hirano, 2005; Nasmyth and Haering, 2009; Onn et al, 2008; Peters et al, 2008; Zheng and Yu, 2015). Cohesin regulates other chromosome-based processes, such as DNA repair, transcription, and chromosome folding (Merkenschlager and Odom, 2013; Wu and Yu, 2012). These other functions of cohesin likely involve the topological entrapment of chromosomes or possibly the extrusion of DNA loops (Barrington et al, 2017; Davidson et al, 2016; Haarhuis et al, 2017)
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