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domain Pol θ, whose function in DNA double-stranded break repair has been more thoroughly established (reviewed by Wood and Doubliè24), one could suppose that Pol ν might play partially similar roles as its paralog. Enhanced repair of double-stranded breaks by an excess of Pol ν in CLL might contribute to maintaining cell survival in managing double-stranded breaks occurring at stalled repli- cation forks upon endogenous replication stress and flu- darabine treatment.
We recently reported that, besides its documented micro- homology-mediated end joining repair activity, Pol θ is capable of regulating the activity of replication origins by interacting with replication origin licensing factors and reg- ulating the timing of replication initiation.25 Whether Pol ν could also regulate origin activity will be another issue to explore in the future since it may also give an alternative mechanistic basis for adaptive response to replication stress.
During disease pathogenesis, CLL leukemic cells suc- cumb to an underlying level of replication stress. This fact is evidenced by the presence of markers of genomic insta- bility, e.g. recurrent chromosomal abnormalities and com- mon somatic mutations. We could hypothesize that, for the CLL cell entering the cell cycle and starting division inside the lymph node pseudofollicule, enhanced expression of POLN could be an adaptive mechanism to limit replication stress caused by a suddenly elevated requirement for dNTP. Our study suggests that the MEC-2 cell line, which shows characteristics of a CLL subclone that has recently exited
the lymph node, expresses a higher level of POLN, allowing leukemic cells to surpass replication stress imposed by treatment with fludarabine. In this context, we could hypothesize that enhanced expression of POLN could be a characteristic acquired in the lymph node as an adaptive mechanism to endogenous replication stress and an advan- tageous trait once the leukemic cell has experienced treat- ment with fludarabine.
In conclusion, the A-family DNA polymerases, whose enhanced expression is observed frequently in solid cancers and, as we reveal here for the first time, in hematologic neo- plasia, could be considered as a response to replication stress, contributing to both cancer progression and thera- peutic resistance, which makes these enzymes attractive targets for future anti-cancer therapies.
Acknowledgments
The authors would like to thank Drs. Richard Wood and Kei- ichi Takata (Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, TX, USA) for the kind gift of MEF POLN cell lines, and Dr. Romain Guieze for providing CLL FMP 2007 RNA samples. Work in the laboratory of JSH is supported by funding from INCa-PLBIO 2016, ANR PRC 2016, Laboratoire d’Excellence Toulouse-Cancer (TOU-CAN) La Ligue Contre le Cancer (Equipe Labellisée 2017) and ITMO Cancer Aviesan within the framework of the Cancer Plan. SG was funded by TOU-CAN and the “Association Action Leucémies and Société Française d’Hématologie”.
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