A novel <i>RAD51</i> variant resulting in Fanconi anemia identified in an infant with multiple congenital anomalies

Geilmann, Shelby; Solstad, Rachel; Palmquist, Rachel; Daboub, Josue Flores; Botto, Lorenzo D.; Grubb, Peter H.; Bonkowsky, Joshua L.; Longo, Nicola; Jenkins, Sabrina Malone

doi:10.1002/ccr3.6810

Cited by 2 publications

(3 citation statements)

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“…Whereas three pathogenic variants in RAD51 have been reported in four cases of an atypical form of FA (FA-R) ( Table 1 ), no cancer predisposition has been associated with these RAD51 mutations to date (cases reported at <4 months and 13, 23, and 9 years of age). This contrasts with the other HR genes mutated in FA [ 22 , 23 , 24 , 25 ]. Collectively, because RAD51 behaves differently than its mediator/accessory proteins for cancerous predisposition, despite its central role in HR, these data reveal the “RAD51 paradox” [ 13 ].…”

Section: Introductionmentioning

confidence: 80%

“…However, the more recent discovery of two non-truncating RAD51 variants (i.e., p.R250Q and p.T134N) [ 26 , 27 ] raised the possibility of alternative pathogenic mechanisms. Molecular pathogenesis may provide insight into the link between the molecular defect and the discrete phenotypes related to human RAD51 mutations, namely, atypical Fanconi anemia (FA-R) [ 22 , 23 , 24 , 25 ], premature ovarian insufficiency [ 30 ], and CMM ( Table 1 and Figure 7 ). No cancer predisposition has been reported in the pathologies caused by RAD51 variants ( Table 1 ).…”

Section: Rad51 Pathogenic Variants In Congenital Mirror Move...mentioning

confidence: 99%

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Noncanonical Roles of RAD51

Thomas

Dubacq

Rabut

et al. 2023

Cells

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Homologous recombination (HR), an evolutionary conserved pathway, plays a paramount role(s) in genome plasticity. The pivotal HR step is the strand invasion/exchange of double-stranded DNA by a homologous single-stranded DNA (ssDNA) covered by RAD51. Thus, RAD51 plays a prime role in HR through this canonical catalytic strand invasion/exchange activity. The mutations in many HR genes cause oncogenesis. Surprisingly, despite its central role in HR, the invalidation of RAD51 is not classified as being cancer prone, constituting the “RAD51 paradox”. This suggests that RAD51 exercises other noncanonical roles that are independent of its catalytic strand invasion/exchange function. For example, the binding of RAD51 on ssDNA prevents nonconservative mutagenic DNA repair, which is independent of its strand exchange activity but relies on its ssDNA occupancy. At the arrested replication forks, RAD51 plays several noncanonical roles in the formation, protection, and management of fork reversal, allowing for the resumption of replication. RAD51 also exhibits noncanonical roles in RNA-mediated processes. Finally, RAD51 pathogenic variants have been described in the congenital mirror movement syndrome, revealing an unexpected role in brain development. In this review, we present and discuss the different noncanonical roles of RAD51, whose presence does not automatically result in an HR event, revealing the multiple faces of this prominent actor in genomic plasticity.

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Section: Introductionmentioning

confidence: 80%

Section: Rad51 Pathogenic Variants In Congenital Mirror Move...mentioning

confidence: 99%

Noncanonical Roles of RAD51

Thomas

Dubacq

Rabut

et al. 2023

Cells

View full text Add to dashboard Cite

show abstract

“…Although RAD51 has historically been recognized as a key recombinase in the strand exchange process during HR, four heterozygous RAD51 mutations— RAD51-T131P , RAD51-A293T , RAD51-Q242R , and RAD51-A294T —have recently been found to cause an FA-like phenotype, designated as FANCR ( 26 , 27 , 28 , 29 , 30 ). Patient-derived cells with these mutations showed hypersensitivity to crosslinking agents.…”

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confidence: 99%