The RecQ helicase family is a group of highly conserved DNA unwinding enzymes described as caretakers of the genome. In humans, loss of function of three of the five members of the RecQ family (RECQ1, WRN, BLM, RECQL4, and RECQL5) is genetically linked with rare cancer predisposition disease (Werner syndrome, Bloom syndrome, and Rothmund-Thomson syndrome). Our goal is to determine common and specialized functions of human RecQ helicases in mechanisms of genome maintenance. The overall focus is on elucidating how impaired function of a specific RecQ protein relates to disease outcomes, including cancer predisposition and premature aging. Loss of RECQ1, the most abundant RecQ homolog in humans, is sufficient to cause genomic instability in mouse and human cells. Work in current funding period identified novel interactions of RECQ1 with proteins that support a role in mechanisms of DNA strand break repair. Furthermore, RECQ1 was enriched at genomic loci that are intrinsically difficult to replicate due to their propensity o form secondary structures. Non-B DNA structures including G4 DNA may present challenges to both replication and transcription. RECQ1 alters gene expression, in part, through its specific binding with G4 motifs predicted to form G4 DNA structures in the target gene promoters in vivo. In this renewal application, we hypothesize that RECQ1 helicase facilitates genome maintenance mechanisms of DNA repair and transcriptional regulation through specific protein partners and recognition of specialized DNA structures.
Our Specific Aims are: to determine the role of RECQ1 in genome maintenance through specific protein partners and chromatin interactions; and to identify RecQ-regulated transcriptome in isogenic background and determine its significance in RecQ functions. Knowledge gained through the proposed study will provide essential framework for exploring in more detail the specific roles of RECQ1 in genome maintenance and its broader significance in cellular homeostasis. Given the importance of genome maintenance as a mechanism to prevent cancer and other genetic diseases, understanding how the loss of a specific RecQ protein may promote genomic instability and cancer susceptibility characteristic of the heritable disease it causes is essential to uncover how individual RecQ homologs work in context of the human health.

Public Health Relevance

RECQ1 belongs to the RecQ family of DNA helicases members of which are associated with rare genetic diseases of premature aging and cancer predisposition in humans. Thus, the functions of RecQ helicases have a direct impact on human health. Elucidating the molecular function(s) of RECQ1 helicase will, therefore, provide important insights into the mechanisms that prevent development of cancer and premature onset of aging. Understanding how the loss of a specific DNA repair protein contributes to genomic instability and cancer susceptibility is fundamental to develop effective anti-tumor therapeutic approaches that are based on DNA damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
5SC1GM093999-08
Application #
9337461
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Reddy, Michael K
Project Start
2016-09-01
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2019-08-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Howard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
Parvathaneni, Swetha; Lu, Xing; Chaudhary, Ritu et al. (2017) RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner. Oncotarget :
Woodrick, Jordan; Gupta, Suhani; Camacho, Sharon et al. (2017) A new sub-pathway of long-patch base excision repair involving 5' gap formation. EMBO J 36:1605-1622
Li, Xiao Ling; Subramanian, Murugan; Jones, Matthew F et al. (2017) Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer. Cell Rep 20:2408-2423
Arora, Arvind; Parvathaneni, Swetha; Aleskandarany, Mohammed A et al. (2017) Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers. Mol Cancer Ther 16:239-250
Sami, Furqan; Gary, Ronald K; Fang, Yayin et al. (2016) Site-directed mutants of human RECQ1 reveal functional importance of the zinc binding domain. Mutat Res 790:8-18
Lu, Xing; Parvathaneni, Swetha; Li, Xiao Ling et al. (2016) Transcriptome guided identification of novel functions of RECQ1 helicase. Methods 108:111-7
Subramanian, M; Francis, P; Bilke, S et al. (2015) A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis. Oncogene 34:1094-104
Sami, Furqan; Lu, Xing; Parvathaneni, Swetha et al. (2015) RECQ1 interacts with FEN-1 and promotes binding of FEN-1 to telomeric chromatin. Biochem J 468:227-44
Sharma, Sudha (2014) An appraisal of RECQ1 expression in cancer progression. Front Genet 5:426
Garige, Mamatha; Sharma, Sudha (2014) Cellular deficiency of Werner syndrome protein or RECQ1 promotes genotoxic potential of hydroquinone and benzo[a]pyrene exposure. Int J Toxicol 33:373-81

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