[초청강연] Dynamic interaction of BRCA2 with the telomeric G-quadruplex guarantees the telomere replication homeostasis

Mice conditionally deficient in the breast cancer susceptibility gene, BRCA2, exhibit
progressive telomere shortening resulting in proliferative defect. Analysis of the MEFs
revealed that Brca2 deficiency resulted in breakdown of stalled replication forks, particularly
at the lagging strand. As G-rich telomere can form G-quadruplex (G4), a four-stranded
compact DNA structure, we asked whether the problem of lagging strand telomere synthesis
upon loss of Brca2 was associated with telomere G4. Using gel shift assay and single
molecule FRET (smFRET), we show that the BRCA2 binds to the telomere G4 in vitro.
BRCA2 exhibited higher affinity to parallel G4, compared to non-parallel G4. Single
molecule FRET analysis revealed that folding and unfolding of parallel G4 is markedly
lower, compared to anti-parallel G4. Moreover, MRE11 was able to attack and resect parallel
G4, which was protected by the addition of BRCA2, suggesting that BRCA2-G4-MRE11
interplay controls telomere replication. Cells depleted of BRCA2 exhibited significant
telomeric damage upon treatment of G4 stabilizer PDS, which was relieved by the
knockdown of MRE11. Taken together, BRCA2 protects telomere replication homeostasis
through binding and controling the dynamicity of telomere G4.