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Sheng Xiao, MD
Associate Research Associate, Brigham and Women's Hospital
Assistant Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115

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Research Narrative:

The role of RPL41 in tumorigenesis and cancer therapy

Ribosomal protein RPL41 encodes a small basic protein with 25 amino acids, which is frequently down-regulated, deleted or mutated in tumors. A FISH analysis of 22 tumor cell lines of various origins revealed RPL41 deletion in 59% of tumors; by a quantitative real-time RT-PCR, RPL41 down regulation was detected in 9 of 12 primary breast cancers in comparison with their paired normal tissues. Sequencing analysis detected frequent mutations in RPL41 promotor in tumors. These studies support a tumor suppression role of RPL41.

Initial studies showed that RPL41 functions in DNA repair pathways and mitosis. By GST-RPL41 pull-down, RPL41 was associated with the regulatory subunit (Ku) of the DNA-dependent protein kinase (DNA-PK), a serine/threonine kinase essential for repairing DNA double strand breaks (DSB) via non-homologous end joining (NHEJ). RPL41 bound to the b-barrel  and polypeptide ring of Ku, a preformed structure through which the DNA is threaded, and significantly increased Ku DNA binding, DNA-PK kinase and NHEJ activity. The physiologic role of RPL41 in NHEJ is suggested by its rapid accumulation in DSB foci after g-irradiation and by the fact that cells with RPL41 knock down had deficiency in both NHEJ and gH2AX foci formation.

Our recent studies also found that cells with RPL41 deficiency had abnormal mitosis including mitotic block at metaphase and failure of cytokinesis. Moreover, a synthetic RPL41 induced mitosis-specific necrotic cell death. Because RPL41 is cell-permeable, we are currently evaluating the possibility of using RPL41 as a systemic anti-cancer drug.