My note on paper: The crosstalk between Wnt/beta-catenin signaling pathway with DNA damage response and oxidative stress: Implications in cancer therapy

Paper: The crosstalk between Wnt/beta-catenin signaling pathway with DNA damage response and oxidative stress: Implications in cancer therapy
(doi:10.1016/j.dnarep.2017.01.003)

Before that we thought wnt signaling might not be related to DNA repair pathway, at all. Then we find this paper writing the review of wnt signaling contributing to DNA damage response and a bit of DNA repair.

wnt signaling:
1. control gene expression
2 cell polarity
3. cell adhesion
4. cell behavior
5. DNA damage response
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Oxidative stress affect the wnt signaling, oxidative stress can cause the DNA lesion
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scope of this paper;
review on the crosstalk of DDR, DNA repair, cellular activities through the wnt signaling pw.

DDR:
1. sense the damage
2. transduce the signal to effector
3. determine the cell fate; cell cycle, fix, or death

wnt signaling
1. determine the cell fate
1.1 cell proliferation
1.2  apoptosis
2. induce DDR through various protein
2.1 H2Ax
2.2 p16-INK4a
2.3 p53
2.3 p21

Scope;
1. wnt signaling + DDR pathway
2. wnt/catenin + regulation of DDR +oxidative induce DNA damage

wnt-signaling;
1. canonical
2. non-canonical
3. wnt/Ca2+ pw (some say it is the subset of non-canocical pw)



Different pws required different co-receptor to go through different downstream signaling network.

canonical pathway; rely on the b-catenin
non-canonical; not rely on beta-catenin once the wnt ligand bind to Fz receptor
wnt/ca2+; upon binding to Fz receptor of wnt; induce the calcium release from the ER

DDR - act through 3 main steps;
1. sense the damage
2. transduce the signal to effector
3. effector takes the action by repairing (if the wound is not severe)

Two types of DNA sensors;
1. db sensor -- rely on MRN cpx (MRE11/RAD50/NBS1)
2. ss sensor; RPA (replication protein A) + RAD9-RAD1-HUS1 (911)

Transducer;
function as amplifying the signal
-- phosphoinositide 3-kinase (PI3K)-like protein kinase family
1.ATM
2.ATR
3.DNA-PKcs

DSB-MRN-ATM-control the cell cycle checkpoint activation+DNA repair
DSB-PKc-initiate NHEJ
SSB-911-ATR-control cell cycle checkpoint and genomic stability

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ATM activation --> gH2Ax-phosphorylation --> signal for DNA lesion and recruit DDR proteins
--
ATR+ATR -- BRCA1, p53-binding protein1 (53BP1)
ATR --> CHK1-Phospho
ATM --> CHK2-Phospho
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Effectors:
p53 and cell division cycle 25 (CDC25)

wnt/b-catenin -- now is attractive target for developing anti-cancer drugs
important point is wnt/catenin pw has majorly participated in regulation and maintenance of cancer stem cells.

Three main ways for targeting the wnt-signaling;
1.tageting receptor or ligand interaction -- Fzd receptor, LRP5/6 coreceptor
2.targeting the cytosolic signaling components -- CK1 family, GSK3beta, Axin
3.targeting the nuclear signaling component - TCF/LEF

Inhibition of DDR proteins;
1. increase the sensitivity toward the chemo-, radiotherapy
2. selectively kill cancer cells with deficiencies in special DNA repair (synthetic lethality)
3. targeting the nuclear signaling components -- TCF/LEF family