SRBD1, a highly conserved factor required for chromosome individualiza-tion in prophase

ABSTRACT: Untangling of DNA is crucial for the individualization of sister chromatids to prevent errors in chromosome segregation in mitosis. Topoisomerase IIα (TOP2A) plays a pivotal role in this process, serving as the primary enzyme responsible for decatenating sister chromatids. The loop-extrusion activity of condensins at the onset of mitosis produces tension on catenanes, directing TOP2A activity towards decatenation. Consequently, condensins and topoisomerase collaborate in the individualization of sister chromatids. Through a haplo-genetic screen in human cells, we identified a highly conserved protein, S1 RNA-binding domain-containing protein (SRBD1), to be absolutely essential for sister chromatid segregation in WT cells but not in Condensin II-deficient cells. The anaphase defects observed upon loss of SRBD1 strikingly resemble the mitotic defects observed when decatenation is perturbed by inhibition or depletion of TOP2A. Moreover, SRBD1 localizes at the central axis of mitotic chromatids, akin to condensins and TOP2A. We show that the activity of SRBD1 is most critical during prophase, corresponding to the peak of Condensin II and TOP2A activity. We found that SRBD1 exhibits direct DNA binding activity with a preference for single-stranded DNA, implying its action at specific genomic structures. Indeed, we found that SRBD1 is strongly enriched at genomic loci associated to transcription and DNA repair. Altogether, we propose that SRBD1 acts at such locations to promote directionality of TOP2A and to prevent the formation of difficult-to-resolve DNA structures, thereby averting severe chromosome missegregations, a function that seems anciently conserved.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Liesbeth Hoekman  

LAB HEAD: Onno Bleijerveld

PROVIDER: PXD054028 | Pride | 2025-03-24

REPOSITORIES: Pride