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Front. Mol. Biosci. | doi: 10.3389/fmolb.2018.00019

Chromatin-Bound Cullin-Ring Ligases: Regulatory Roles in DNA Replication and Potential Targeting for Cancer Therapy

Sangmin Jang1, Christophe E. Redon1 and  Mirit I. Aladjem1*
  • 1National Cancer Institute (NIH), United States

Cullin-RING (Really Interesting New Gene) E3 ubiquitin ligases (CRLs), the largest family of E3 ubiquitin ligases, are functional multi-subunit complexes including substrate receptors, adaptors, cullin scaffolds and RING-box proteins. CRLs are responsible for ubiquitination of ~20% of cellular proteins and are involved in diverse biological processes including cell cycle progression, genome stability and oncogenesis. Not surprisingly, cullins are deregulated in many diseases and instances of cancer. Recent studies have highlighted the importance of CRL-mediated ubiquitination in the regulation of DNA replication/repair, including specific roles in chromatin assembly and disassembly of the replication machinery. The development of novel therapeutics targeting the CRLs that regulate the replication machinery and chromatin in cancer is now an attractive therapeutic strategy. In this review, we summarize the structure and assembly of CRLs and outline their cellular functions and their diverse roles in cancer, emphasizing the regulatory functions of nuclear CRLs in modulating the DNA replication machinery. Finally, we discuss the current strategies for targeting CRLs against cancer in the clinic.

Keywords: DNA Replication, Chromatin, ubiquitin ligases, Cancer, therapy

Received: 05 Dec 2017; Accepted: 12 Feb 2018.

Edited by:

Zvi Kelman, National Institute of Standards and Technology, United States

Reviewed by:

Dana Branzei, IFOM - The FIRC Institute of Molecular Oncology, Italy
Karim Mekhail, University of Toronto, Canada  

Copyright: © 2018 Jang, Redon and Aladjem. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mirit I. Aladjem, National Cancer Institute (NIH), Rockville, United States, aladjemm@mail.nih.gov