Renier Velez-Cruz, Ph.D.

Assistant Professor

Midwestern University
Chicago College of Osteopathic Medicine
Department of Biochemistry
555 31st St.
Downers Grove, IL 60515
Office: Science Hall 421-E
Phone: (630) 515-6047


B.S. Chemistry University of Puerto Rico-Mayaguez Campus 1999
Ph.D. Biochemistry Vanderbilt University 2005


The importance of chromatin remodeling for DNA double-strand break repair, transcription, and cancer therapy

The integrity of our genetic material is constantly challenged by endogenous and exogenous chemicals, as well as DNA metabolic processes such as DNA replication, transcription, and recombination. These chemicals and processes can generate DNA double-strand breaks (DSBs), one of the most cytotoxic and tumorogenic DNA lesions. The repair of DSBs is important for both, the prevention of cancer, as well as the efficacy of cancer therapy. On one hand, defects in the repair pathways that correct these lesions result in increased levels of mutations, genomic instability, and cancer. On the other hand, defects in these repair pathways also sensitize these cells to many types of cancer therapies that kill cells by generating DSBs. Our laboratory is interested in the identification of novel factors important for the repair of DSBs, the characterization of the function of such factors in the repair process, and the application of this knowledge towards the improvement of cancer therapies. Chromatin remodelers and modifiers have been identified as a group of genes highly mutated or deleted in many cancers, and important for the repair process.

The DNA is wrapped around a group of proteins known as histones and these proteins hinder the repair process by blocking access to the DNA. Histones can be modified by acetylation, methylation, phosphorylation and ubiquitylation. These modifications are thought to alter the chromatin environment (either relax or compact chromatin) by changing the interactions between the histones and the DNA. These modifications can also serve as a mark that can be recognized by other proteins, which can then be recruited to these marks and catalyze other changes in chromatin structure at a specific locus. Chromatin remodelers are a group of proteins that alter chromatin structure by pushing and sliding nucleosomes and thus modulating access to DNA. Chromatin remodelers are important for all processes that require access to DNA, such as replication, transcription, and repair.

We are particularly interested in the SWI/SNF family of chromatin remodelers, which are protein complexes composed of 10-15 different subunits. These complexes are mutated in 20% of cancers. SWI/SNF complexes are characterized by the presence of an ATPase subunit (either BRM or BRG1), which induces chromatin remodeling by hydrolyzing ATP.  SWI/SNF complexes are classified into two subgroups: BRG1/BRM-associated factors (BAF) and polybromodomain BRG1-associated factor (pBAF). Both of these complexes are characterized by different subunit composition (Figure 1). Moreover, multiple subunits of these complexes are mutated at very high frequencies in a variety of cancers. We have shown that BRG1 is important for homologous recombination (HR) repair and we are currently trying to elucidate the mechanism by which BRG1 functions in HR. Since other SWI/SNF subunits are mutated in cancers, we want to determine what is the role of these other subunits in HR.

Finally, the transcriptional response to DNA damage is also of critical importance for the efficacy of cancer therapy. Cancer cells treated with an effective dose of a DNA damaging agent initiate transcriptional programs that result in either cell death (apoptosis) or an indefinite cell cycle arrest (senescence). SWI/SNF complexes are known to be important for the transcription of multiple genes involved in these transcriptional programs. We are interested in avaluating how the transcriptional response to DNA damage changes in SWI/SNF-deficient cells, or cells deficient in specific SWI/SNF subunits that are highly mutated in cancer.

Research projects:

Our laboratory is interested in the function of the SWI/SNF chromatin remodelers in the repair of DNA double strand breaks and the transcriptional response to DNA damage. Our long-term goal is to identify other chromatin remodelers or modifiers that affect the response to cancer therapies (Figure 2).

Project I: We have shown that BRG1 is important for the DNA end resection step of homologous recombination. We want to dissect the specific role BRG1 plays at DSBs and how this ATPase stimulates DNA end resection.

Project II: BRG1, ARID1A, ARID2, and PBRM1 are among the most commonly mutated SWI/SNF subunits in a variety of human cancers. BRG1 is the only subunit with a catalytic role within the SWI/SNF complex (in addition to BRM thus far). We want to determine whether the other non-catalytic subunits play a role in the repair of DSBs and what is the role these subunits play in this process.

Project III: The majority of cancer therapies kill tumor cells by damaging their DNA, and thus the transcriptional response to anti-cancer agents is very important for the efficacy of these drugs. Since SWI/SNF complexes are also important for transcription, we want to study how these complexes and inactivation of various subunits of these complexes affect the transcriptional response to DNA damage. 

Research Opportunities: We welcome students from the Masters in Biomedical Science and the Master of Arts in Biomedical Sciences programs to explore reserch opportunities in our lab either through a thesis, research electives, or work-study programs. We also welcome medical students through the Keneth E. Suarez Fellowship during the summer. Regardless of your program, if you are interested in our research contact Dr. Velez-Cruz.

Selected Publications

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1.Vélez-Cruz R, Manickavinayaham S, Biswas AK, Clary RW, Premkumar T, Cole F, Johnson DG. Genes Dev. 2016 Nov 15;30(22):2500-2512.

The CSB repair factor is overexpressed in cancer cells, increases apoptotic resistance, and promotes tumor growth. Caputo M, Frontini M, Velez-Cruz R, Nicolai S, Prantera G, Proietti-De-Santis L. DNA Repair (Amst). 2013 Apr 1;12(4):293-9.

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells. Vélez-Cruz R, Zadorin AS, Coin F, Egly JM. Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):E212-20.

CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination. Latini P, Frontini M, Caputo M, Gregan J, Cipak L, Filippi S, Kumar V, Vélez-Cruz R, Stefanini M, Proietti-De-Santis L. Cell Cycle. 2011 Nov 1;10(21):3719-30.

NER factors are recruited to active promoters and facilitate chromatin modification for transcription in the absence of exogenous genotoxic attack. Le May N, Mota-Fernandes D, Vélez-Cruz R, Iltis I, Biard D, Egly JM. Mol Cell. 2010 Apr 9;38(1):54-66.

Deletion of 5' sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome. Laugel V, Dalloz C, Stary A, Cormier-Daire V, Desguerre I, Renouil M, Fourmaintraux A, Velez-Cruz R, Egly JM, Sarasin A, Dollfus H. Eur J Hum Genet. 2008 Mar;16(3):320-7.

Exocyclic DNA lesions stimulate DNA cleavage mediated by human topoisomerase II alpha in vitro and in cultured cells. Vélez-Cruz R, Riggins JN, Daniels JS, Cai H, Guengerich FP, Marnett LJ, Osheroff N. Biochemistry. 2005 Mar 15;44(10):3972-81.

DNA ligation catalyzed by human topoisomerase II alpha. Bromberg KD, Vélez-Cruz R, Burgin AB, Osheroff N. Biochemistry. 2004 Oct 26;43(42):13416-23.

Invited Articles:

The Retinoblastoma (RB) Tumor Suppressor: Pushing Back against Genome Instability on Multiple Fronts. Vélez-Cruz R, Johnson DG. Int J Mol Sci. 2017 Aug 16;18(8).

Cockayne syndrome group B (CSB) protein: at the crossroads of transcriptional networks. Vélez-Cruz R, Egly JM. Mech Ageing Dev. 2013 May-Jun;134(5-6):234-42.

E2F1 and p53 transcription factors as accessory factors for nucleotide excision repair. Vélez-Cruz R, Johnson DG. Int J Mol Sci. 2012 Oct 19;13(10):13554-68.

Topoisomerases: Eukaryotic and Prokaryotic Type II. Vélez-Cruz, R. and Osheroff, N. Encyclopedia of Biological Chemistry (W. Lennarz, and M.D. Lane, eds.) Elsevier, Oxford, (2004) Vol. 1, pp. 806-811.