Oncogenic and antioncogenic signals arising from the depletion of pol eta and FANCD2 in the xeroderma pigmentosum variant disease

FEDERICO MB, CAMPANA C, PAVIOLO N, CALZETTA N, DE LA VEGA MB AND GOTTIFREDI V

Suzhou

Conferencia; Cold Spring Harbor Asia Conference of DNA Metabolism, Genome Stability and Human Disease; 2018

Cold Spring harbor

Oncogenic and antioncogenic signals arising from the depletion of pol eta in the xeroderma pigmentosum variant diseaseMaría Belén Federico, Carolina Campana, Natalia Paviolo, Nicolás Calzetta, María Belén de la Vega and Vanesa Gottifredi.Xeroderma Pigmentosa Variant is a cancer prone syndrome caused by the loss of translesion polymerase eta, which is specialized in the DNA synthesis across cyclobutane pyrimidine dimers (CDP). Pol eta replicates DNA across CPDs with outstanding accuracy. As a consequence, pol eta loss causes an increase in the rate of point mutations by less accurate specialized polymerases. However, DNA replication across UV damaged-DNA may not only be inaccurate but also, it could be inefficient as suggested by plasmid-based assays performed in cells depleted from pol eta. The consequences of the inefficiency of TLS in pol eta-depleted cells are currently unknown.Here we show that in the absence of pol eta, the DNA replication stress caused by UV irradiation is persistent when compared to control samples. Double strand breaks and cell death also increase in pol eta depleted cells after UV irradiation. Surprisingly, despite the recruitment of homologous recombination markers to replication factories, such DNA repair pathway plays no apparent role in the DDR response of UV-irradiated pol-eta depleted cells. Instead, pol eta knock down or depletion causes persistent cell cycle arrest in S phase, which is accompanied with massive accumulation of single stranded DNA (ssDNA). Strikingly, the elimination of the MRE11 nuclease reduces ssDNA accumulation and cell death in UV-irradiated pol eta-depleted samples. Together, our results demonstrate that whilst pol eta elimination may certainly promote cancerogenesis triggered by error prone TLS, it can also trigger cell death mediated by ssDNA-accumulation in cell persistently arrested in S phase. This information can be of use when exploring the use of TLS inhibition for cancer treatment.