**5. DNA DSB repair**

*DNA - Damages and Repair Mechanisms*

Some small molecules such as S- adenosylmethionine can methylate bases endogenously. According to recent study from almost 4000 residues generated per day 7-methylguanine (7 meG) is most important. 7-methylguanine base is relatively harmless and doesnot show any cytotoxic properties. Whereas endogenously produced 3-methyladenine (3-meA) which are few hundred in number are building

The base sugar bonds in DNA are relatively labile and several thousands of bases are lost each day in human cells under physiological conditions [12]. Purines are lost more easily than pyrimidines. Base loss sites probably represent the most frequent

Mismatches can occur in DNA due to the incorrect incorporation by DNA polymerases, damage to the nucleotide precursors in the cellular nucleotide pool or

SSBs arise when diester bond between phosphate and the deoxyribose breaks. After the breakage of phosphodiester bond separation of both the strands occurs causing the water molecule to penetrate the breach. This process causes breakage of

When two complementary strand of double DNA breaks in a location at a point less than 3 nucleotides is known as DNA DSBs. DSBs are considered as the most deleterious type of damage because both the complementary strands are damaged and it is very difficult for the internal repair mechanism of the cell to handle this type of damage. The factors leading to the formation of DSB include endogenous factors that are associated with physiological processes occurring in the cell and the

In the presence of endogenous DNA damage, a cell can survive up to some extent, however the concentrated damages accelerated by exogenous agents such as ionizing radiations, radiomimetic drugs, ultra-violet radiations, and carcinogens can induce permanent changes. These changes lead to cancer or severely impaired cellular functioning and poor repair efficiency which may eventually cause cell death by triggering apoptosis or irreversible cell growth arrest [25]. Ionizing radiations generate ROS, which cause oxidative damage to DNA. The most important

various forms of DNA damage occur. Exposure of DNA to ionizing radiations result in a number of different lesions in DNA such as base damage, single strand breaks and double strand breaks [9, 10, 26]. DNA DSBs present a major threat to the integrity of chromosomes and viability of cells. Unrepaired or incorrectly repaired DSBs

(hydroxyl radical) and H2O2 (hydrogen per-

) reacts with DNA and as a result,

block of DNA replication and should be efficiently repaired [21].

*2.3.2 Methylation*

*2.3.3 Hydrolysis*

damage in human cells.

by damage to DNA [13].

**3. Single strand breaks (SSBs)**

hydrogen bonds between the bases [5].

**4. Double strand breaks (DSBs)**

ROS are O2• (superoxide radical), OH•

oxide). The highly reactive hydroxyl radical (OH•

exogenous ones [22–24].

*2.3.4 Mismatches*

**104**

Humans cells have two major DSBs repair mechanisms i.e. homology directed repair (HDR) and non-homologous end joining (NHEJ) [23]. However, in recent years a new mechanism called as alternative non-homologous end joining (A-NHEJ) has evolved (**Figure 2**). The selection criteria for DNA repair mechanism depends upon cell type, cell cycle phase and damage threshold. The non-dividing cells do not have the option of undergoing HDR but dividing cells can use all the three repair mechanisms with some conditions. The condition is NHEJ and A-NHEJ both can act in all the phases of cell cycle, however, the HDR is only able to act at S/ G2 phase of the cell cycle [29].

#### **5.1 Homologous recombination pathway**

Homologous recombination pathway (HR) generally repairs the DNA lesions in late S or G2 phase of cell cycle. HR pathway is a series of interrelated pathways that participate in the repair of different types of DNA damages like double strands breaks (DSBs), interstrand cross links and DNA gaps. Several studies have shown

**Figure 2.** *Double strand break repair pathway choice.*

### *DNA - Damages and Repair Mechanisms*

that HR is an error-free pathway. This pathway is known as error-free because it occurs only S and G2 phases of cell cycles. In these phases of cell cycles sister chromatids are more easily available and can be used as template to synthesize new strands of DNA [30]. HR pathway is essential for cell division in higher eukaryotes to prevent recombination between non identical sequences. HR plays an important role in DNA replication for duplicating the genome and also in telomere maintenance for the recovery of broken replication fork [31–34].

HR accomplishes through following steps:

