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Antagonistic roles of canonical and alternative-RPA in disease-associated tandem CAG repeat instability

ABSTRACT: Ongoing CAG expansions in Spinocerebellar ataxia type 1 (SCA1) and Huntington disease (HD) brains exacerbate disease. Expansions involve aberrant repair of mutagenic slipped-DNAs, formed from single-stranded DNAs. Whether singlestranded DNA-binding proteins prevent or facilitate expansions is unknown. We assessed canonical RPA (RPA1-RPA2-RPA3) and Alternative-RPA (RPA1-RPA4- RPA3), containing primate-specific RPA4. RPA is essential for all DNA metabolism. Alt-RPA has undefined functions. Alt-RPA is upregulated 10-fold in HD and SCA1 patient brains. RPA enhances, while Alt-RPA blocks, correct repair of slipped-CAGs. RPA, but not Alt-RPA, efficiently binds and melts slipped-DNAs. RPA enhances, while Alt-RPA blocks, removal of excess slipped-DNAs by FAN1 nuclease. Protein-protein interactomes reveal unique and shared partners of RPA and Alt-RPA, including expansion-driving proteins. RPA-overexpression in SCA1 mice inhibits CAG expansions in brains, rescuing neuron morphology and motor phenotypes. Modulating repeat mutations is one example involving antagonistic Alt-RPA↔RPA interactions, illuminating questions as to which RPA-mediated processes are also modulated by AltRPA.

INSTRUMENT(S): autoflex

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Early Embryonic Cell

SUBMITTER: Jennifer Raisch

LAB HEAD: Francois-Michel Boisvert

PROVIDER: PXD044158 | Pride | 2023-10-13

REPOSITORIES: Pride

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			Action	DRS
	Carla_293FT_ctrl_N1_Slot2-1_1_3410.d.7z	Other
	Carla_293FT_ctrl_N2_Slot2-2_1_3411.d.7z	Other
	Carla_293FT_ctrl_N3_Slot2-3_1_3412.d.7z	Other
	Carla_293FT_ctrl_Slot1-10_1_2902.d.7z	Other
	Carla_293FT_ctrl_Slot1-37_1_2272.d.7z	Other

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