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Ubiquitin E3 ligases UBR4, UBR5 and HUWE1 protect human genome integrity by targeting cancer-associated APOBEC3 deaminases for degradation

ABSTRACT: Members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family play crucial roles as viral restriction factors, yet some APOBEC3 (A3) members drive harmful hypermutation in humans, contributing to cancer. These cancer-associated A3 members have reduced RNA-mediated retention in the cytosol, and therefore can drive nuclear DNA mutation. We show that specifically major cancer-associated members are rapidly turned-over by proteasomes, indicating the existence of cellular pathways marking cancer-associated A3s for degradation, thereby protecting cellular genomic DNA from hypermutation. Through genetic and proteomic screening UBR4, UBR5 and HUWE1 were identified as degraders of cancer-associated A3 proteins, thereby limiting A3-driven hypermutation. Mechanistically, UBR5 and HUWE1 recognize the unengaged RNA-binding interface of cancer-associated A3B and A3H-I, promoting their proteasomal degradation. Depletion or mutation of the E3 ligases in cell models and cancer samples increased A3-driven hypermutation. Our findings highlight UBR4, UBR5 and HUWE1 as crucial factors in maintaining human genome stability.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Markus Hartl

LAB HEAD: Gijs Versteeg

PROVIDER: PXD051267 | Pride | 2025-12-22

REPOSITORIES: Pride

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			Action	DRS
	20210804_E3_RSLC6_Budroni_Versteeg_MPL_A3HII_EPOX_VB22_30p.raw	Raw
	20210804_E3_RSLC6_Budroni_Versteeg_MPL_A3HII_EPOX_VB23_30p.raw	Raw
	20210804_E3_RSLC6_Budroni_Versteeg_MPL_A3HII_EPOX_VB24_30p.raw	Raw
	20210804_E3_RSLC6_Budroni_Versteeg_MPL_A3HI_EPOX_VB10_30p.raw	Raw
	20210804_E3_RSLC6_Budroni_Versteeg_MPL_A3HI_EPOX_VB11_30p.raw	Raw

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