Advancing our knowledge of pericentromeric heterochromatin repair is a high impact investment for improving human health: heterochromatin is a poorly characterized region that comprises nearly a third of the human genome; double-strand break (DSB) repair failures in this region affect not just specific genes, but also genome-wide stability; and the likelihood of failures is high because of the many repeated sequences that characterize this domain. Despite the foundational importance of characterizing these processes, DSB repair mechanisms in heterochromatin are largely understudied. We discovered a specialized pathway that promotes faithful homologous recombination (HR) repair in heterochromatin while preventing aberrant recombination, effectively isolating heterochromatic repair sites to the nuclear periphery before strand invasion. We have recently identified several components required for this process, including nuclear actin filaments (F-actin) an myosins, and chromatin-associated nucleoporins, but the regulation and function of these components remain poorly understood. Deregulation of heterochromatin repair is likely one of the most underestimated and powerful sources of tumorigenesis, and identifying the components involved is essential for understanding cancer etiology and developing more effective strategies for therapeutic intervention. Our central hypothesis is that F-actin, myosins, nucleoplasmic nucleoporins, and phase separation are essential regulators of heterochromatin repair dynamics, and that SUMOylation participates in coordinating their function repair progression. We will combine a wealth of super resolution imaging, genetic and biochemical approaches to investigate the molecular mechanisms involved in these process. Expected positive outcomes of this research include the systematic identification of the molecular machinery that protects heterochromatin from massive genome rearrangements, enabling successful completion of HR repair. These studies are also expected to illuminate missing links between nuclear architecture and dynamics, phase separation, repair progression, and the stability of repeated DNA sequences. These results will have an important positive impact by identifying crucial safeguard mechanisms used by normal cells to protect the genome from environmental threats. Mutations in these pathways result in genome instability, tumorigenesis, and reduced life span. Thus, we expect that the proposed studies and future research will trigger exciting advancements in the prevention, early detection, and treatment of cancer and other human diseases associated with genome instability and aging- related disorders.

Public Health Relevance

Understanding DNA repair is central to understanding the mechanisms responsible for cancer formation, and identifying more effective targets for early cancer detection and treatment. Our studies aim to illuminate DNA repair in heterochromatin, a poorly characterized domain occupying 30% of the human genome. Even though heterochromatin is highly prone to aberrant recombination that triggers genome instability and tumorigenesis, surprisingly little is known about repair in this domain.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Keane-Myers, Andrea
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University of Southern California
Schools of Arts and Sciences
Los Angeles
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Caridi, Christopher P; D'Agostino, Carla; Ryu, Taehyun et al. (2018) Nuclear F-actin and myosins drive relocalization of heterochromatic breaks. Nature 559:54-60
Caridi, Christopher P; Delabaere, Laetitia; Tjong, Harianto et al. (2018) Quantitative Methods to Investigate the 4D Dynamics of Heterochromatic Repair Sites in Drosophila Cells. Methods Enzymol 601:359-389
Caridi, P Christopher; Delabaere, Laetitia; Zapotoczny, Grzegorz et al. (2017) And yet, it moves: nuclear and chromatin dynamics of a heterochromatic double-strand break. Philos Trans R Soc Lond B Biol Sci 372:
Delabaere, Laetitia; Ertl, Henry A; Massey, Dashiell J et al. (2017) Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells. Aging Cell 16:320-328
Li, Qingjiao; Tjong, Harianto; Li, Xiao et al. (2017) The three-dimensional genome organization of Drosophila melanogaster through data integration. Genome Biol 18:145
Amaral, Nuno; Ryu, Taehyun; Li, Xiao et al. (2017) Nuclear Dynamics of Heterochromatin Repair. Trends Genet 33:86-100
Delabaere, Laetitia; Chiolo, Irene (2016) ReiNF4rcing repair pathway choice during cell cycle. Cell Cycle 15:1182-3
Ryu, Taehyun; Bonner, Melissa R; Chiolo, Irene (2016) Cervantes and Quijote protect heterochromatin from aberrant recombination and lead the way to the nuclear periphery. Nucleus 7:485-497
Ryu, Taehyun; Spatola, Brett; Delabaere, Laetitia et al. (2015) Heterochromatic breaks move to the nuclear periphery to continue recombinational repair. Nat Cell Biol 17:1401-11