Biology Reference
In-Depth Information
Holliday junction resolvase), the eukaryotic ResA Holliday junction resolvase
was identified.
457
It appears that ResA copurifies with RAD51C-XRCC3 iso-
lated from human cells.
446,457
Recently, another group of Holliday junction resolvases, namely, the SLX1-
SLX4 complex, were identified (
Table I
; Refs.
458-461
). Even though Slx1 was
conserved, conventional homology searches did not indicate a conservation of
Slx4 outside the yeast genome.
420,445,462
By more refined in silico analyses,
human SLX4 was identified as BTBD12, which was the ortholog
Drosophila
MUS312 and fungal Slx4.
458-460,463
In a separate study, BTBD12 was identified
as a phosphorylation substrate of ATM/ATR kinases.
459,464
SLX1 possesses the
endonuclease domain for Holliday junction cleavage, while SLX4 acts as a
protein-interacting scaffold that interacts with multiple nucleases that cleave
Holliday junctions both symmetrically and asymmetrically.
420,445
In fact, SLX4
has been implicated in multiple genome maintenance pathways including repli-
cation and repair.
445,458-460,463
Because SLX4 interacts with other Holliday
junction resolvases such as MUS81-EME1, when the SLX1-SLX4 complex
was isolated from human cells, symmetrical cleavage of Holliday junctions was
not observed.
458,459,464
However, bacterially expressed, the SLX1-SLX4 hetero-
dimer with a truncated SLX4 region that does not interact with MUS81-EME1
did possess symmetrical cleavage ability of Holliday junctions.
445,458,459,464
Among the many interacting partners of mammalian SLX4 are proteins of
diverse functions. These include the endonucleases SLX1, ERCC4-ERCC1,
and MUS81-EME1; mismatch repair heterodimer MSH2-MSH3; telomere
proteins TRF2/RAP1; and polo-like kinase PLK1.
445,458-460,464
XI. Homeologous Recombination: The Interplay Between
Mismatch Repair and HR
Mismatch repair (MMR) is a conserved process that plays an important
role in maintaining genome integrity by correcting DNA mismatches formed
during replication and recombination.
465-467
MMR ensures that HR occurs
between perfectly homologous sequences and suppresses recombination betw-
een sequences that contain partial homology (homeologous recombination).
465
Genetic studies in budding yeast indicate that even a single mismatch reduces
the recombination rates by at least fourfold compared to recombination betw-
een substrates of perfect homology.
468,469
In yeast, Msh2-Msh6, Msh2-Msh3,
and Mlh1-Pms1 MMR heterodimers as well as Rad1-Rad10 and Exo1 nucle-
ases and helicases Sgs1 and Srs2 have been implicated in suppressing home-
ologous recombination.
29,470-473
In mice and human cells, a BLM (Sgs1
homolog) deficiency still suppresses homeologous recombination. However,
