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PARP1-modulated chromatin remodeling is a new target for cancer treatment

Abstract

Cancer progression requires certain tumorigenic mutations in genes encoding for different cellular and nuclear proteins. Altered expressions of these mutated genes are mediated by post-translational modifications and chromatin remodeling. Chromatin remodeling is mainly regulated by the chromatin remodeling enzyme complexes and histone modifications. Upon DNA damage, Poly-(ADP-ribose) Polymerase1 (PARP1) plays a very important role in the induction of chromatin modifications and activation of DNA repair pathways to repair the DNA lesion. It has been targeted to develop different anti-cancer therapeutic interventions and PARP inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for clinical use. But it has been found that the cancer cells often develop resistance to these PARP inhibitors and chromatin remodeling helps in enhancing this process. Hence, it may be beneficial to target PARP1-mediated chromatin remodeling, which may allow to reverse the drug resistance. In the current review, we have discussed the role of chromatin remodeling in DNA repair, how PARP1 regulates modifications of chromatin dynamics, and the role of chromatin modifications in cancer. It has also been discussed how the PARP1-mediated chromatin remodeling can be targeted by PARP inhibitors alone or in combination with other chemotherapeutic agents to establish novel anti-cancer therapeutics. We have also considered the use of PARG inhibitors that may enhance the action of PARP inhibitors to target different types of cancers.

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Availability of data and materials

All the information mentioned in this review article are available on the internet.

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Acknowledgements

The authors would like to acknowledge the Department of Biotechnology (DBT), Government of India, for providing research funding to CNK. They would also like to thank the Indian Council of Medical research (ICMR), Government of India, and Government of Ethiopia for providing research fellowships to SS and SM, respectively.

Funding

This work was partly funded by the Department of Biotechnology (DBT), Government of India (102/IFD/SAN/703/2018–2018).

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SS and SM contributed equally to the conception, design, and drafting of the manuscript. CNK critically reviewed the manuscript and approved the final submitted version.

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Correspondence to Chanakya Nath Kundu.

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Sinha, S., Molla, S. & Kundu, C.N. PARP1-modulated chromatin remodeling is a new target for cancer treatment. Med Oncol 38, 118 (2021). https://doi.org/10.1007/s12032-021-01570-2

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Keywords

  • Cancer
  • Chromatin remodeling
  • DNA repair
  • PARP1
  • PARP inhibitors