Tarek Abbas
Assistant Professor of Radiation Oncology and
  Biochemistry & Molecular Genetics
Ph.D., City University of New York (CUNY)
The Ubiquitin system and human diseases


Cellular homeostasis is governed through the balanced production and termination of critical cellular proteins controlling various physiological processes, such as cellular proliferation and migration. In many instances, these processes depend on specific enzymatic activities that are invariably controlled through the action of cellular proteins and cofactors that are actively synthesized, modified or destroyed to achieve optimal activity. A key question is how does a cell sense the requirement to terminate the life of a given protein and what are the consequence of derailment of this sensing mechanism or failure of the proteolytic machinery to respond to these signals?

The polyubiquitination of cellular proteins is a common posttranslational modification by which proteins are actively eliminated through proteolysis. The process is highly regulated, often depends on complex signaling network and its deregulation frequently results in the development of human diseases, including cancer.

ATP-dependent polyubiquitination of proteins and their subsequent degradation by the proteasome is involved in all aspects of cell physiology. The highly coordinated process ensures timely down-regulation of proteins thereby controlling cellular activity and maintaining cell and tissue homeostasis. Polyubiquitination is frequently triggered by posttranslational modifications (such as phosphorylation) of the target substrate thus signaling its proteolytic degradation. The process involves tagging proteins with the small 76 amino-acid ubiquitin moiety on specific lysine residue in the target substrate protein thus marking it for proteolysis via the 26S proteasome. Polyubiquitination involves three distinct and consecutive enzymatic steps; i. Ubiquitin activation by an E1 ubiquitin-activating enzyme; ii. The transfer of activated (AMP-charged) ubiquitin from the E1 enzyme to an E2 ubiquitin-conjugating enzyme, and iii. Ubiquitin transfer from the E2 enzyme to the substrate through the activity of an E3 ubiquitin ligase.

Polyubiquitination of cellular proteins is reversible, and the removal of ubiquitin chains from substrate proteins is carried by a class of cystein proteases, with the exception of JAMMs, which are members of the zinc metalloproteases, collectively termed “deubiquitinases” or “DUBs”. DUBs play a pivotal role as regulators of the turnover rate, activation, recycling and localization of many proteins and thus, are essential for regulating several signaling pathways and cellular homeostasis.

Research in my laboratory is focused on understanding the role of the ubiquitin system in the development and progression of human cancer as well as its role in promoting cellular responses to current therapeutic agents, with a particular focus on ionizing radiation and the development of resistance to anti-cancer agents. We are particularly interested in investigating the regulated process of protein ubiquitylation and proteolysis of DNA sensing and repair molecules. Currently, there are a handful of examples where DNA repair proteins are regulated at the level of ubiquitin-dependent proteolysis and current evidence suggest that many others are yet to be identified specifically in post-repair recovery. Thus, we hope that this line of investigation will lead to the genetic and biochemical characterization of novel pathways that can be potentially exploited for therapeutic intervention.

A second focus of our research is to understand how the activity of the various components of the ubiquitin system is regulated and how deregulation of such activity impact or modulate downstream cellular responses. Our long-term goal is to identify some of the basic principles that govern cellular homeostasis and safeguard against disease development, and ultimately applying knowledge and technology in preventing or treating cancer when these safeguarding mechanisms fail to function.

Selected References

Shibata E, Abbas T, Huang X, Wohlschlegel JA, Dutta A. (2011) "Selective ubiquitylation of p21 and Cdt1 by UBCH8 and UBE2G ubiquitin-conjugating enzymes via the CRL4Cdt2 ubiquitin ligase complex." Mol Cell Biol. 31(15):3136-45. Epub 2011 May 31. [PubMed]

Abbas T, Dutta A. (2011) "CRL4Cdt2: master coordinator of cell cycle progression and genome stability." Cell Cycle. Jan 10:241-9. Epub 2011 Jan 15. [PubMed]

Abbas T, Shibata E, Park J, Jha S, Karnani N, Dutta A. (2010) "CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation." Mol Cell. Oct 40:9-21. [PubMed]

Abbas T, Dutta A. (2009) "p21 in cancer: intricate networks and multiple activities." Nat Rev Cancer. 9:400-14. [PubMed]

Terai K, Abbas T, Jazaeri AA, Dutta A. (2010) "CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis." Mol Cell. Jan 37:143-9. [PubMed]

Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A. (2008) "PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex." Genes Dev. Sep 22(18):2496-506. [PubMed]

Abbas T, White D, Hui L, Yoshida K, Foster DA, Bargonetti J. (2004) "Inhibition of human p53 basal transcription by down-regulation of protein kinase Cdelta." J Biol Chem. Mar 279(11):9970-7. Epub 2003 Dec 29. [PubMed]

Abbas T, Olivier M, Lopez J, Houser S, Xiao G, Kumar GS, Tomasz M, Bargonetti J. (2002) "Differential activation of p53 by the various adducts of mitomycin C." J Biol Chem. Oct 277(43):40513-9. Epub 2002 Aug 14. [PubMed]