Our finding that five of six cancer-associated CSB mutations, D1425N, Q1444H, A1445S, R1462L and G1484R, differentially affect CSB’s ability to regulate RNAPII association with ACTB, GAPDH and RPL13A genes as well as to promote cell survival in response to cisplatin-induced DNA damage suggests the complexity of the impact of CSB somatic mutations. The gene discussed is ACTB; the disease is cancer.