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2016 ; 7
(5
): 485-497
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Cervantes and Quijote protect heterochromatin from aberrant recombination and
lead the way to the nuclear periphery
#MMPMID27673416
Ryu T
; Bonner MR
; Chiolo I
Nucleus
2016[Sep]; 7
(5
): 485-497
PMID27673416
show ga
Repairing double-strand breaks (DSBs) is particularly challenging in
heterochromatin, where the abundance of repeated sequences exacerbates the risk
of ectopic recombination and chromosome rearrangements. In Drosophila cells,
faithful homologous recombination (HR) repair of heterochromatic DSBs relies on a
specialized pathway that relocalizes repair sites to the nuclear periphery before
Rad51 recruitment. Here we show that HR progression is initially blocked inside
the heterochromatin domain by SUMOylation and the coordinated activity of two
distinct Nse2 SUMO E3 ligases: Quijote (Qjt) and Cervantes (Cerv). In addition,
the SUMO-targeted ubiquitin ligase (STUbL) Dgrn, but not its partner dRad60, is
recruited to heterochromatic DSBs at early stages of repair and mediates
relocalization. However, Dgrn is not required to prevent Rad51 recruitment inside
the heterochromatin domain, suggesting that the block to HR progression inside
the domain and relocalization to the nuclear periphery are genetically separable
pathways. Further, SUMOylation defects affect relocalization without blocking
heterochromatin expansion, revealing that expansion is not required for
relocalization. Finally, nuclear pores and inner nuclear membrane proteins
(INMPs) anchor STUbL/RENi components and repair sites to the nuclear periphery,
where repair continues. Together, these studies reveal a critical role of
SUMOylation and nuclear architecture in the spatial and temporal regulation of
heterochromatin repair and the protection of genome integrity.