Somatic cell reprogramming to induced pluripotent stem cells (iPSCs) holds great promise for revolutionizing tissue repair and regenerative medicine. However, achieving high reprogramming efficiency remains challenging due to various endogenous or exogenous barriers. One major obstacle is DNA replication stress arising from rapid cell proliferation during iPSC reprogramming, which results in genomic instability and markedly reduced reprogramming efficiency. The Plk1-interacting checkpoint helicase PICH; also known as DNA excision repair protein ERCC-6-like (ERCC6L), a member of the SNF2 ATPase family, is pivotal in maintaining genomic stability by promoting sister chromatid disjunction upon replication stress. Our previous work revealed that PICH is essential for maintaining the genomic stability of embryonic hematopoietic stem cells, but whether and how PICH participates in iPSC reprogramming remains elusive. We show that PICH deficiency induces genomic instability and drastically reduces the efficiency of iPSC generation. Overexpression of Pich improves iPSC reprogramming efficiency by alleviating replication stress. Furthermore, PICH cooperates with telomere-associated protein RIF1, another protein required for sister chromatid disjunction, to maintain genomic stability in iPSCs, thereby enhancing reprogramming efficiency. Taken together, these results reveal a previously unknown role of PICH in facilitating the reprogramming of iPSCs via maintaining genomic stability under replication stress, and provide a new strategy for improving iPSC reprogramming efficiency.
Zhang et al. (Tue,) studied this question.