INHIBITION OF TRANSLESION DNA SYNTHESIS AS A STRATEGY TO SENSITIZE CANCER CELLS TO DNA-DAMAGING AGENTS

M. BELÉN DE LA VEGA; VANESA GOTTIFREDI; SABRINA F. MANSILLA

Buenos Aires

Congreso; Frontiers in Bioscience 3; 2018

Cancer cells proliferate more rapidly than normal cells and are thussensitive to DNA-damaging agents used in traditional chemotherapy. These agentstarget cells with high proliferation rate by producing DNA damage that impairsreplication and causes cell death. The efficacy of anticancer treatments is,however, highly influenced by the cellular capacity to respond to DNA damage.One central mechanism that can enable cancer cells to survive is TranslesionDNA Synthesis (TLS), where specialized DNA polymerases bypass lesionsencountered during DNA replication, a situation where replicative DNApolymerases normally stall. Therefore, inhibiting TLS would be deleterious tothese cells when used in combination with DNA-damaging agents. We havepreviously identified p21, the cyclin-CDK inhibitor, as the first globalinhibitor of TLS. A stabilized version of p21 (sp21) can inhibit therecruitment of TLS polymerases to replication factories after DNA damage andthis is dependent on its PCNA-binding domain. We have recently found a smallerversion of p21 (sPIR) which is sufficient to robustly inhibit the recruitmentof TLS polymerases to replication factories post ultraviolet (UV) radiation. Byusing a non-replicative lentivirus system as an overexpression tool, we havefound that both sp21 and sPIR cause accumulation of molecular markersassociated with replicative stress and increase genomic instability and celldeath in the context of DNA-damage inductors. Lately, we have also found thatco-inhibition of TLS and other protein with a pivotal role in in the S-phasecheckpoint efficiently synergize to enhance cell death.