INTS3, a subunit of the integrator complex, plays crucial roles in multiple biological processes. It is involved in DNA repair, particularly in homologous recombination-dependent repair of double-strand breaks (DSBs) and in ATM-dependent signaling pathways [1,5,6,7,8,9]. It also has a role in RNA-related functions such as RNA polymerase II termination [4]. Additionally, abnormal INTS3 splicing and reduced expression are associated with leukaemogenesis [2], and it functions as an anti-apoptotic RNA-binding protein in colorectal cancer [3].

CRISPR-Cas9 screening in colorectal cancer cells showed that deletion/depletion of INTS3 triggered apoptosis, destabilized pro-apoptotic gene transcripts, and delayed cell growth in vivo, highlighting its importance in cancer cell survival [3]. In the context of DNA damage response, the INTS3-MISE-hSSB1 complex is key for ATM activation and RAD51 recruitment to DNA damage foci [5]. RPA70 depletion leads to the formation of sub-nuclear foci by hSSB1 and INTS3, which recruit the ATR-ATRIP checkpoint complex to sites of genomic stress [7]. Perturbation of INTS3 dimerization and disruption of the INTS3/INTS6 interaction impair the DSB repair process [9].

In summary, INTS3 is essential for DNA repair, regulation of apoptosis in cancer cells, and has implications in leukaemogenesis. Studies using loss-of-function models like CRISPR-Cas9 knockout in cancer cells and investigations of protein-protein interactions related to INTS3 have provided valuable insights into its role in these biological processes and disease conditions.