SENP1 Decreases RNF168 Phase Separation to Promote DNA Damage Repair and Drug Resistance in Colon Cancer

Abstract

The DNA damage response (DDR) is essential for the maintenance of genomic stability. Protein posttranslational modifications play pivotal roles in regulating the DDR process. Here, we found that SUMOylated RNF168 undergoes liquid-liquid phase separation (LLPS), which restricts the recruitment of RNF168 to DNA damage sites, reduces RNF168-catalyzed H2A ubiquitination, restrains 53BP1 in nuclear condensates, and ultimately impairs non-homologous DNA end joining (NHEJ) repair efficiency. SENP1 was identified as a specific deSUMOylase of RNF168, and it was highly expressed in colorectal adenocarcinoma. In response to DNA damage, SENP1 decreased RNF168 SUMOylation and prevented RNF168 from forming nuclear condensates, thus promoting damage repair efficiency and cancer cell resistance to DNA damaging agents. Moreover, high SENP1 expression correlated with poor prognosis in cancer patients, and SENP1 depletion sensitized cancer cells to chemotherapy. In summary, these findings reveal DDR is suppressed by SUMOylation-induced LLPS of RNF168 and suggest that SENP1 is a potential target for cancer therapy.

A novel risk signature based on liquid-liquid phase separation-related genes reveals prognostic and tumour microenvironmental features in clear cell renal cell carcinoma

“…Various cellular activities involve “phase separation”, and therefore abnormal phase separation often leads to the development of many diseases. For example, in colorectal adenocarcinoma, SENP1 reduces the SUMOylation of RNF168 when DNA damage occurs, facilitating its LLPS, enhancing non-homologous end joining (NHEJ) repair efficiency, and consequently strengthening cancer cell resistance to DNA-damaging agents [ 26 ]. CircASH2 enhances the LLPS of nuclear Y-box binding protein 1 (YBX1) in hepatocellular carcinoma, and also enhances the attenuation of the primary target protein tropomyosin 4 (TPM4) transcripts, thereby altering the tumor cytoskeleton structure to inhibit HCC metastasis [ 27 ].…”

Galangin cooperates with oxaliplatin to inhibit the proliferation and invasion of colorectal cancer cells by targeting CBX3

“…Even though chemotherapy is initially successful, Oxa resistance eventually develops and poses a serious challenge to CRC treatment, with a poor clinical prognosis. Drug-resistant cancer cells typically show reduced drug absorption, increased drug e ux, greater detoxi cation of chemotherapeutic medicines, and/or enhanced DNA damage repair (Wei et al 2023). To improve the clinical prognosis of patients with colorectal cancer, it is imperative to identify techniques for overcoming oxaliplatin resistance.…”

SUMO and the DNA damage response

“…RNF168 interacts with ubiquitinated H1 [ 75 ] and in turn, ubiquitinates H2A/H2AX at K13/K15 which can recruit 53BP1 or BRCA1-BARD1 (breast cancer type 1 susceptibility protein — BRCA1 associated RING domain 1) [ 77–80 ]. PIAS4 SUMO1ylates and SENP1 deSUMOylates RNF168, which maintain correct 53BP1 foci expansion and limit NHEJ [ 81 , 82 ]. The PIAS4-dependent SUMO1 conjugation wave detected at DSBs [ 48 , 83 ] has been proposed to be composed of mixed SUMO1-SUMO2/3 linkages specifically generated by PIAS4 [ 29 ] ( Figure 5 , subsection 2).…”