18PCNA sliding clamp binds factors through which histone deposition, chromatin 19 remodeling, and DNA repair are coupled to DNA replication. PCNA also directly binds 20 Eco1/Ctf7 acetyltransferase, which in turn activates cohesins and establishes cohesion between 21 nascent sister chromatids. While increased recruitment thus explains the mechanism through 22 36 During S phase, the cellular genome duplicates and each sister chromatid becomes 37 tethered together to ensure proper inheritance of the genome during mitosis. Sister chromatid 38 tethering is maintained by cohesin, a complex comprised of Smc1, Smc3, and 39Mcd1/Scc1/RAD21 along with auxiliary subunits Pds5, Scc3/Irr1, Rad61/WAPL and, in 40 vertebrate cells, Sororin [1][2][3][4][5][6][7]. Cohesin deposition onto DNA requires the cohesin loader, 41 comprised of Scc2,4, which functions through a large part of the cell cycle but is essential during 42 S phase for cohesins to participate in sister chromatin tethering [8,9]. Deposition onto chromatin, 43 however, is not sufficient for cohesion. Eco1/Ctf7 (herein Eco1) is an acetyltransferase that 44 converts chromatin-bound cohesins, through acetylation of Smc3 cohesin subunit, to a tethering 45 competent state [3,[10][11][12][13]. Early studies coupled this process of cohesion establishment to the 46 DNA replication factor PCNA [10]. PCNA directly binds and recruits Eco1 to the DNA 47 replication fork [14][15][16], suggesting that establishment is coordinated with numerous processes 48 (histone deposition, chromatin remodeling, DNA repair and translesion synthesis) directed by 49 PCNA and regulated through PCNA post-translational modifications [17][18][19][20]. Elevated 50 recruitment to the DNA replication fork thus provides a plausible explanation for PCNA-51 dependent suppression of eco1 mutant cell growth defects [10,15]. The repertoire of DNA 52 replication factors (Chl1, Ctf4, Ctf18, MCM2-7, for example) implicated in cohesion 53 establishment regulation has grown substantially [15,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], highlighting the fundamental and 54 highly conserved nature through which cohesion establishment is obligatorily coordinated with 55 DNA replication. 56Further complicating the relationship between PCNA, Eco1 and cohesins are the 57 additional roles played beyond sister chromatid tethering [1,5,10,[36][37][38][39][40][41][42][43][44][45][46][47]. For instance, cohesin 58 4 functions in both DNA replication restart during S phase and high fidelity DNA repair after S 59 phase [48][49][50]. Cohesin is recruited to stalled DNA replication forks during S phase, as well as to 60 rDNA and telomeric regions that experience prescribed pauses during replication [51][52][53]. 61Cohesin is similarly recruited to sites of DNA damage to promote high fidelity repair by 62 ensuring proximity to the undamaged sister template [49,54,55]. Intriguingly, once recruited to 63 stalled replication forks and sites of DNA damage, cohesin must ultimately dissociate from DNA 64 to promote repl...
