Variants of the human RAD52 gene confer defects in ionizing radiation resistance and homologous recombination repair in budding yeast

Clear, Alissa; Manthey, Glenn M.; Lewis, Olivia; Lopez, Isabelle Y.; Rico, Rossana; Owens, Shannon N; Negritto, M. Cristina; Wolf, Elise W; Xu, Jason; Kenjić, Nikola; Perry, J. Jefferson P.; Adamson, Aaron W.; Neuhausen, Susan L.; Bailis, Adam M.

doi:10.15698/mic2020.10.732

Cited by 4 publications

(6 citation statements)

References 97 publications

(139 reference statements)

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“…Previously a RAD52 S346* truncation was associated with reduced breast cancer risk in carriers of germline BRCA2 mutations [ 22 ]. Subsequent experiments have shown that the S346* truncation affects RAD52 oligomerization and HR repair when expressed in budding yeast [ 70 ]. This truncation also shows decreased nuclear localization because it loses the C-terminus domain where the NLS sequences are ( Fig 3 ) [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…This truncation also shows decreased nuclear localization because it loses the C-terminus domain where the NLS sequences are ( Fig 3 ) [ 22 ]. In human cells but not budding yeast S346* also shows SSA defects [ 22 , 70 ]. The authors suggest that in the absence of BRCA2 function, repair relies on RAD52 which promotes mutagenic SSA.…”

Section: Resultsmentioning

confidence: 99%

“…The other mutants (G48D, M78I, G125C, and A146V) did not show any significant impact on the protein structure ( S2 Fig ). A RAD52 G59R mutation identified in Black women with breast cancer was shown to have decreased association with DNA [ 70 ]. We also modeled the G59R mutation [ 70 ] to see if this result could be explained structurally.…”

Section: Resultsmentioning

confidence: 99%

“…A RAD52 G59R mutation identified in Black women with breast cancer was shown to have decreased association with DNA [ 70 ]. We also modeled the G59R mutation [ 70 ] to see if this result could be explained structurally. The model of this mutant displayed a more extended loop structure that sterically clashes with the DNA bound to the outer site ( Fig 5E and 5F ).…”

Section: Resultsmentioning

confidence: 99%

“…association with DNA [70]. We also modeled the G59R mutation [70] to see if this result could be explained structurally.…”

Section: Plos Onementioning

confidence: 99%

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Pan-cancer analysis of co-occurring mutations in RAD52 and the BRCA1-BRCA2-PALB2 axis in human cancers

et al. 2022

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In human cells homologous recombination (HR) is critical for repair of DNA double strand breaks (DSBs) and rescue of stalled or collapsed replication forks. HR is facilitated by RAD51 which is loaded onto DNA by either BRCA2-BRCA1-PALB2 or RAD52. In human culture cells, double-knockdowns of RAD52 and genes in the BRCA1-BRCA2-PALB2 axis are lethal. Mutations in BRCA2, BRCA1 or PALB2 significantly impairs error free HR as RAD51 loading relies on RAD52 which is not as proficient as BRCA2-BRCA1-PALB2. RAD52 also facilitates Single Strand Annealing (SSA) that produces intra-chromosomal deletions. Some RAD52 mutations that affect the SSA function or decrease RAD52 association with DNA can suppress certain BRCA2 associated phenotypes in breast cancers. In this report we did a pan-cancer analysis using data reported on the Catalogue of Somatic Mutations in Cancers (COSMIC) to identify double mutants between RAD52 and BRCA1, BRCA2 or PALB2 that occur in cancer cells. We find that co-occurring mutations are likely in certain cancer tissues but not others. However, all mutations occur in a heterozygous state. Further, using computational and machine learning tools we identified only a handful of pathogenic or driver mutations predicted to significantly affect the function of the proteins. This supports previous findings that co-inactivation of RAD52 with any members of the BRCA2-BRCA1-PALB2 axis is lethal. Molecular modeling also revealed that pathogenic RAD52 mutations co-occurring with mutations in BRCA2-BRCA1-PALB2 axis are either expected to attenuate its SSA function or its interaction with DNA. This study extends previous breast cancer findings to other cancer types and shows that co-occurring mutations likely destabilize HR by similar mechanisms as in breast cancers.

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Section: Resultsmentioning

confidence: 99%