biostudies-literatureUnknown13(1)Paniagua IProtection of stalled replication forks is essential to prevent genome instability, a major driving force of tumorigenesis. Several key regulators of DNA double-stranded break (DSB) repair, including 53BP1 and RIF1, have been implicated in fork protection. MAD2L2, also known as REV7, plays an important role downstream of 53BP1/RIF1 by counteracting resection at DSBs in the recently discovered shieldin complex. The ability to bind and counteract resection at exposed DNA ends at DSBs makes MAD2L2/shieldin a prime candidate for also suppressing nucleolytic processing at stalled replication forks. However, the function of MAD2L2/shieldin outside of DNA repair is unknown. Here we address this by using genetic and single-molecule analyses and find that MAD2L2 is required for protecting and restaNature communications5167https://www.ebi.ac.uk/biostudies/studies/S-EPMC9458726biostudies-literatureMAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner.PMC9458726Tayeh ZCerutti AFalcone MHernandez Perez SPaniagua IJacobs JJLfalseMAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner.Protection of stalled replication forks is essential to prevent genome instability, a major driving force of tumorigenesis. Several key regulators of DNA double-stranded break (DSB) repair, including 53BP1 and RIF1, have been implicated in fork protection. MAD2L2, also known as REV7, plays an important role downstream of 53BP1/RIF1 by counteracting resection at DSBs in the recently discovered shieldin complex. The ability to bind and counteract resection at exposed DNA ends at DSBs makes MAD2L2/shieldin a prime candidate for also suppressing nucleolytic processing at stalled replication forks. However, the function of MAD2L2/shieldin outside of DNA repair is unknown. Here we address this by using genetic and single-molecule analyses and find that MAD2L2 is required for protecting and resta2022-01-01T00:00:00Z2022 Sep2025-04-05T10:25:45.089Z2025-04-05T10:25:45.089ZS-EPMC94587263607589710.1038/s41467-022-32861-5