Fission yeast Srr1 and Skb1 promote isochromosome formation at the centromere

Abstract

Rad51 faithfully repairs DNA damage, whereas Rad52 promotes non-canonical homologous recombination leading to gross chromosomal rearrangements (GCRs). However, the GCR mechanism remains unclear. Here we find that fission yeast Srr1/Ber1 and Skb1/PRMT5 arginine methyltransferase promote isochromosome formation at centromeres. srr1 and skb1 mutations reduce GCR rates. Physical analysis of GCR products reveals that srr1 and skb1 specifically reduce isochromosome formation. Remarkably, srr1 and rad51 additively increase DNA damage sensitivity, suggesting that Srr1 promotes Rad51-independent DNA damage response prone to isochromosome formation. In contrast, loss of Skb1 does not increase damage sensitivity and, intriguingly, reduces chromosome loss in rad51∆ cells, suggesting that Skb1 forms DNA structures that need to be processed by Rad51 or else chromosomes become unstable. Srr1 and Skb1 act in the Rad52-dependent GCR pathway, while Srr1 also has a role in the Rad52-independent pathway. This study has uncovered unprecedented roles for Srr1 and Skb1 in GCRs at centromeres.