Gene Regulation + Cell Cycle

What is the Central Dogma of Molecular Biology?

RNA transcription involves the action of an enzyme complex, an _______________, that can assemble an ______________ whose sequence corresponds to the “coding” strand of DNA.

RNA polymerase, RNA polymer

Gene expression can be regulated by families of ______________, proteins that bind to specific DNA ____________ regions and either prevent or allow transcription to occur.

transcription factors, promoter

In other instances, transcription may be activated by a signal transduction pathway involving an…

extracellular ligand, receptors at the cell surface, and intracellular signal transduction pathways.

How are extracellular signals transduced to an instruction for mitosis, or cell division?

Example: growth factor receptor activation, leading to activation of transcription of “immediate-early genes” myc and fos. These in turn can regulate the transcription of “delayed response genes,” including those that control the cell cycle (the sequence of events that constitute cell division, or mitosis).

What happens during Gap 1 (G1) of the cell cycle?

Cells grow in size and accumulate ATP

What happens during S phase of the cell cycle?

Chromosomes are replicated, transcription ceases

What happens during Gap 2 (G2) phase of the cell cycle?

ATP restored in preparation for distribution of chromosomes and organelles between the “daughter” cells

Landmark phases of the cell cycle are controlled by what?

Protein complexes of Cyclins and Cyclin-dependent protein kinases (Cdk), whose appearance and disappearance is closely regulated

Cdks act on…

protein substrates to activate machinery associated with each step

Cyclins and Cdks are regulated by…

phosphorylation and interaction with other proteins —> fidelity and timing of multiple aspects of the process are monitored

Among the genes whose transcription is activated by ________ or growth factors are those controlling expression of the _______________, which in turn control expression of those involved in the transition from G1 to S phase

mitogens, Cdks associated with G1

Regulation of gene expression and mitosis, including entry into or progression through the cell cycle, occur by mechanisms similar to those in other signaling pathways, such as…

• Amplification cascades involving reversible protein phosphorylation

• Formation of multi-subunit complexes

• Negative feedback

What transcriptional errors can occur?

At the level of RNA transcription, gene expression can be dys-regulated with respect to the timing or magnitude of transcription rate, or the fidelity of base-pairing

With respect to transcriptional errors, RNA polymerase has the capacity to…

detect and repair mismatches

Consequences of DNA damage

• DNA repair

• Cell cycle arrest

• Transcription of damage-responsive genes

• Apoptosis - regulated cell death

DNA damage can be detected by…

specialized pathways in nucleus

What happens if cell cycle checkpoints fail?

allows persistence of mutations and genomic rearrangements that may result in genomic instability —> major factor in birth defects and in development of genetic diseases, notably cancer

Certain mutations in proteins controlling M-phase

Produce failure of the checkpoint —> cell finishes mitosis but produces daughter cells with too many or too few chromosomes (aneuploidy), one of the hallmarks of cancer cells

What are spindle checkpoints?

• Detect failure of spindle fibers to attach to kinetochores + arrest cell in metaphase until all kinetochores are attached correctly

• Detect improper alignment of spindle itself + block cytokinesis

• Trigger apoptosis if damage is irreparable

What is necrosis?

cell death via disordered lysis of cells, with consequent inflammatory responses

All steps of cell division in order

1. Interphase: nucleus replicates its DNA and centrosomes

2. Interphase-prophase transition: chromatin begins to coil

3. Prophase: chromatin continues to coil and supercoil, making chromatin more compact, chromosomes consist of identical, paired chromatids

4. Prometaphase: nuclear envelope breaks down, kinetochore microtubules appear + interact with polar microtubules of spindle, resulting in movement of chromosomes

5. Metaphase: duplicated centromere regions connecting paired chromatids become aligned at cell’s equator

6. Anaphase: centromeres divide, new chromosomes move toward poles

7. Telophase: separating chromosomes reach poles, passes into next interphase as nuclear envelopes and nucleoli re-form and chromatin becomes diffuse