ESCO1/2's roles in chromosome structure and interphase chromatin organization

Abstract

ESCO1/2 acetyltransferases mediating SMC3 acetylation and sister chromatid cohesion (SCC) are differentially required for genome integrity and development. Here we established chicken DT40 cell lines with mutations in ESCO1/2, SMC3 acetylation, and the cohesin remover WAPL. Both ESCO1 and ESCO2 promoted SCC, while ESCO2 was additionally and specifically required for proliferation and centromere integrity. ESCO1 overexpression fully suppressed the slow proliferation and centromeric separation phenotypes of esco2 cells but only partly suppressed its chromosome arm SCC defects. Concomitant inactivation of ESCO1 and ESCO2 caused lethality owing to compromised mitotic chromosome segregation. Neither wapl nor acetyl-mimicking smc3-QQ mutations rescued esco1 esco2 lethality. Notably, esco1 esco2 wapl conditional mutants showed very severe proliferation defects associated with catastrophic mitoses and also abnormal interphase chromatin organization patterns. The results indicate that cohesion establishment by vertebrate ESCO1/2 is linked to interphase chromatin architecture formation, a newly identified function of cohesin acetyltransferases that is both fundamentally and medically relevant.

Liberating cohesin from cohesion

“…An outstanding question in the field is how tension is generated between sister kinetochores that can be on the order of 1 µm apart. Kawasumi et al (2017) show that the distance between sister centromeres is increased in esco2 mutants. Thus, cohesin is required for centromere integrity.…”

“…In this way, sister centromeres are "pushed" apart, biasing kinetochores to the surface of the chromosome. Kawasumi et al (2017) show that ESCO1/2 modification of cohesin plays a role in regulating this function in mammalian cells as well.…”

“…What the Kawasumi et al (2017) study shows is that cohesin rings and their regulation participate in genome organization as cells cycle through division. In interphase, ESCO1/2 together with Wapl work to reduce the amount of cohesin (more cohesin in the mutants).…”

“…Considering the diversity of their function, it is a major challenge to identify specific protein deficiencies that map to specific disorders. Targeted mutations with critical quantitative analysis as performed in Kawasumi et al (2017) exemplify how we make progress in this exciting yet nonintuitive field.…”

“…As we explore the genome in time and space, we are coming to appreciate that these ring complexes exhibit a diverse array of functions and significantly more functional overlap than their names imply. Kawasumi et al (2017) explore ESCO1/2 function through targeted mutations in chicken DT40 cells, where they discovered roles for these acetyltransferases in establishing chromosome territories during interphase and centromere organization in metaphase. These functions do not rely on cohesin acetylation (K105, K106) and force us to broaden our thinking of how protein ring complexes and their regulation might function in higher-order chromosome organization.…”