Cancer arises from the accumulation of small changes (mutations) in different genes in our normal epithelial cells (for example in the prostate, breast or colon) that eventually result in uncontrolled proliferation of the cells. When normal epithelial cells divide, they require the normal function of many cellular proteins and nucleic acids at certain points in the cell-division process. Cancer cells use these same cellular factors for their proliferation and mis-regulation of these factors help them escape the restraints to proliferation.

Both normal and cancer cells require the actions of many enzymes (DNA replication factors) for copying the DNA in the chromosomes. A cell will stop dividing if it cannot copy its chromosomes or will divide incompletely replicated chromosomes and induce chromosomal damage. One area of research in my laboratory is to identify the factors necessary for DNA replication initiation and determine how they are regulated. We also identify the consequences of mis-regulation of these factors on genomic stability and the cell-cycle. In addition, we use modern tools of genomics to identify sites on human chromosomes that begin the process of DNA replication and how these sites change between different cells.

An independent area of research focuses on small RNAs present in our cells. MicroRNAs and other short RNAs are now known to have profound effects on gene expression and are hypothesized to affect cell proliferation. To study this process in detail we explore the role of microRNAs in inducing quiescence as proliferating myoblasts differentiate into mature muscle fibers. Androgen deprivation is the primary mode of therapy of advanced prostate cancer, and recurrence of the disease is associated with androgen-independence. Thus, we also study how microRNAs and other short RNAs change when androgen-dependent prostate cancer cells are induced to become quiescent by androgen deprivation. Collectively these studies will elucidate how microRNAs and other short RNAs influence cell proliferation.

Selected References

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]

Lee YS, Dutta A. (2008) "MicroRNAs in Cancer." Annu Rev Pathol. Sep [Epub ahead of print] [PubMed]

Jha S, Shibata E, Dutta A. (2008) "Human Rvb1/Tip49 is required for the histone acetyltransferase activity of Tip60/NuA4 and for the downregulation of phosphorylation on H2AX after DNA damage." Mol Cell Biol. 28:2690-700. Epub 2008 Feb 19. [PubMed]

Zhu W, Ukomadu C, Jha S, Senga T, Dhar SK, Wohlschlegel JA, Nutt LK, KornbluthS, Dutta A. (2007) "Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication." Genes Dev. Sep 21(18):2288-99. Epub 2007 Aug 30. [PubMed]

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Karnani N, Taylor C, Malhotra A, Dutta A. (2007) "Pan-S replication patterns and chromosomal domains defined by genome-tiling arrays of ENCODE genomic areas." Genome Res. 17:865-76. [PubMed]

Lee YS, Dutta A. (2007) "The tumor suppressor microRNA let-7 represses the HMGA2 oncogene." Genes Dev. May 21:1025-30. Epub 2007 Apr 16. [PubMed]

Machida YJ, Dutta A. (2007) "The APC/C inhibitor, Emi1, is essential for prevention of rereplication." Genes Dev. Jan 21:184-94. [PubMed]

Kim HK, Lee YS, Sivaprasad U, Malhotra A, Dutta A. (2006) "Muscle-specific microRNA miR-206 promotes muscle differentiation." J Cell Biol. Aug 174:677-87. Epub 2006 Aug 21. [PubMed]

Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A. (2006) "UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation." Mol Cell. 23:589-96. [PubMed]

Zhu W, Dutta A. (2006) "An ATR- and BRCA1-mediated Fanconi anemia pathway is required for activating the G2/M checkpoint and DNA damage repair upon rereplication." Mol Cell Biol. 26(12):4601-11. [PubMed]

Takeda DY, Shibata Y, Parvin JD, Dutta A. (2005) "Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells." Genes Dev. Dec 19(23):2827-36. [PubMed]