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The interplay of the translocase activity and protein recruitment function of PICH in ultrafine anaphase bridge resolution and genomic stability
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2024-12-20 , DOI: 10.1093/nar/gkae1249 Nannan Kong, Kun Chen, Primrose Chanboonyasitt, Huadong Jiang, Ka Yan Wong, Hoi Tang Ma, Ying Wai Chan
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2024-12-20 , DOI: 10.1093/nar/gkae1249 Nannan Kong, Kun Chen, Primrose Chanboonyasitt, Huadong Jiang, Ka Yan Wong, Hoi Tang Ma, Ying Wai Chan
Incomplete sister centromere decatenation results in centromeric ultrafine anaphase bridges (UFBs). PICH (PLK1-interacting checkpoint helicase), a DNA translocase, plays a crucial role in UFB resolution by recruiting UFB-binding proteins and stimulating topoisomerase IIα. However, the involvement of distinct PICH functions in UFB resolution remains ambiguous. Here, we demonstrate that PICH depletion in non-transformed diploid cells induces DNA damage, micronuclei formation, p53 activation, G1-phase delay and cell death. Whole-genome sequencing reveals that segregation defects induced by PICH depletion cause chromosomal rearrangements, including translocations and inversions, emphasizing its significance in preserving genomic integrity. Furthermore, a PICH mutant that impairs UFB recruitment of BLM and RIF1 partially inhibits UFB resolution while a translocase-inactive mutant (PICHK128A) fails to resolve UFBs. Notably, expression of PICHK128A inhibits single-stranded UFB formation and induces hypocondensed chromosomes. We propose that PICH’s translocase activity plays a dual role in promoting UFB resolution by facilitating the generation of single-stranded UFBs and stimulating topoisomerase IIα.
更新日期：2024-12-20
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