Biomedical Engineering Reference
In-Depth Information
, that inactivates BRCA proteins [1].
A heat map showing the gene profile of tumors with and without
the
2. Upregulation of
EMSY
mutation differentiated specific patterns for BRCA-like (BL)
and non-BRCA-like (NBL) tumors with 94% accuracy in 61 patients.
In this study, BRCAness was determined by sensitivity to platinum
and the presence of RAD51 foci, as a marker of HR. The BRCAness
profile also correlated with PARP inhibitor sensitivity. Interestingly,
in this study, two of the three tumors that reverted from nonfunctional
to functional
BRCA
status after treatment with cisplatin, coinciding
with cisplatin resistance, also showed the change in the genetic
expression profile. The BL gene expression profile correlated with
improved DFS and OS and was an independent prognostic indicator
in multivariate analyses [12].
BRCA
15.3
Poly (ADP-Ribose) Polymerase (PARP)
PARPs are a family of proteins with enzymatic properties, scaffolding
properties, and recruiting abilities for other necessary DNA repair
proteins. PARP affects repair for SSBs, primarily as part of BER [19],
PARP 1 and PARP 2 are the best studied to date of these proteins,
and the targets of most of the PARP inhibitors presently under
development for cancer therapy [18]. PARP proteins were initially
identified in 1963 [48,16] and PARP inhibitors were proposed to
enhance alkylator activity in 1980 [17]. In response, it produces PAR
and transfers it to acceptor proteins on the PARP itself and other
proteins involved in DNA repair. The negative charge of PAR causes
PARP 1 to lose its affinity for DNA. PAR then recruits other repair
proteins to the damaged DNA site. PARP 1 retains the largest amount
of PAR. PAR also binds XRCC1, the scaffolding protein. PAR regulates
histone H1 binding to chromatin, allowing the chromatin to relax.
PARP is involved in methylation and transcription of genes coding
for cell cycle and stress response, including
. PAR attaches DNA
polymerase β to the DNA break site to replace the missing bases.
Finally, PAR combines with DNA ligase III to seal the DNA [48-50].
The six proteins fall into three groups:
p53
Group 1: PARP 1, PARP 2, and PARP 3;
Group 2: PARP 4, also called vault PARP;
Group 3: tankyrase (TNKS) and TNKS2, also known as PARP 5
and PARP 6, respectively.
