Biochemistry for Pharmacy and Biomedical Sciences

Biochemistry for Dental Medicine

Biochemistry for Optometry

Human Genetics

Targeting DNA repair and transcription to enhance the efficacy of cancer therapies.

Radiotherapy and the vast majority of chemotherapeutic agents that are currently used to treat cancer kill tumor cells by damaging their DNA. DNA double strand breaks (DSBs) are one of the most toxic lesions caused by many of these agents. My laboratory studies the cellular mechanisms that repair these DNA lesions and how chromatin affects these repair pathways. We are particularly interested in the homologous recombination (HR) repair pathway. We have identified the SWI/SNF chromatin remodeling complex as important for HR. We specifically identified the ATPase subunit within this complex (BRG1) as important for HR.

SWI/SNF chromatin remodeling complexes contain 10-15 subunits and the function of the majority of these subunits is unknown. Various subunits within these complexes are mutated at high frequencies in multiple types of cancer. We have now identified various other subunits (in addition to BRG1) within the SWI/SNF chromatin remodeling complexes as important for HR and we are in the process of dissecting the function of these subunits in this repair pathway. We intend to do a systematic study of the function of multiple subunits within the SWI/SNF chromatin remodeling complexes. This work could allow us to identify specific cancer types with mutations in SWI/SNF subunits that would be sensitive to specific chemotherapeutic regimens.

In addition to the repair of DSBs, the transcriptional response to DNA damage has important implications for the efficacy of cancer therapies. SWI/SNF chromatin remodeling complexes are known to play important roles in transcription regulation. As a long-term goal, my lab intends to study the function of SWI/SNF chromatin remodeling complexes in the transcriptional response to DNA damage. We will focus our attention to the subunits within these complexes that do not play an important role in the repair of DSBs.

PEER REVIEWED ARTICLES:

Hays, E., Nettleton, E., Carter, C., Morales, M., Vo, L., Passo, M., Vélez-Cruz, R. “The SWI/SNF ATPase BRG1 stimulates DNA end resection and homologous recombination by reducing nucleosome density at DNA double strand breaks and by promoting the recruitment of the CtIP nuclease.” Cell Cycle (2020), 12:1-19.

Manickavinayaham S, Vélez-Cruz R, Biswas AK, Bedford E, Klein BJ, Kutateladze TG, Liu B, Bedford MT, Johnson DG. “E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair.” Nat. Commun. (2019), 10(1): 4951-65.

Vélez-Cruz, R., Manickavinayaham, S., Biswas, A.K.,  Clary, R.W., Premkumar, T., Cole, F. and Johnson, D.G. “RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment BRG1.” Genes Dev. (2016) 30(22): 2500-12.

Vélez-Cruz, R., Zadorin, A., Coin, F. and Egly, J.M. “Sirt1 suppresses RNA synthesis after UV irradiation in XP-D /CS cells.” Proc. Natl. Acad. Sci. U.S.A. (2013) 110(3):E212-20.

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

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

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

Laugel, V., Dalloz, C., Stary, A., Cormier-Daire, V., Desguerre, I., Renouil, M., Velez-Cruz, R., Egly, J.M., Sarasin, A., Dollfus, H. "Deletion of 5' sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome." Eur. J. Hum. Gen. (2008) 16, 320-327.

Vélez-Cruz, R., Riggins, J.N., Daniels, J.S., Marnett, L.J., Cai, H., Guengerich, F.P., and Osheroff, N. “Exocyclic DNA Lesions Stimulate DNA Cleavage Mediated by Human Topoisomerase IIα In Vitro and in Cultured Cells.” Biochemistry. (2005) 44, 3972–3981.

Bromberg, K.D., Vélez-Cruz, R., Burgin, A.B., and Osheroff, N. “DNA Ligation Catalyzed by Human Topoisomerase IIa.” Biochemistry. (2004) 43, 13416–13423.

INVITED ARTICLES:

Sadek, M, Sheth, A, Zimmerman, G, Hays, E, Vélez-Cruz, R. The role of SWI/SNF chromatin remodelers in the repair of DNA double strand breaks and cancer therapy. Front. Cell Dev. Biol. (2022); 10:1071786.

Manickavinayaham, S., Vélez-Cruz, R., Biswas, A.K., Chen, J., Guo, R., and Johnson, D.G. “The E2F1 Transcription Factor and RB Tumor Suppressor Moonlight as DNA Repair Factors.” Cell Cycle (2020) 19(18): 2260-69.

Vélez-Cruz, R*. and Johnson, D.G. “The retinoblastoma (RB) tumor suppressor: pushing back against genomic instability on multiple fronts.” Int. J. Mol. Sci. (2017) 18(8): 1776 (*co-corresponding author)

Vélez-Cruz, R*. and Egly, J.M. “Cockayne syndrome group B protein: at the cross roads of transcriptional networks” Mech. Aging Dev. (2012) 134(5-6):234-42. (*co-corresponding author)

Vélez-Cruz, R. and Johnson, D.G. “E2F1 and p53 as accessory factors for nucleotide excision repair.” Int. J. Mol. Sci. (2012)13(10), 13554-13568.

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

American Association for Cancer Research (AACR)

R15 CA267864                                                                             (R. Vélez-Cruz, PI)    8/22-7/25

NIH-NCI “The role of SWI/SNF chromatin remodelers in homologous recombination and genome stability”